Heterocyclic antagonists of prostaglandin d2 receptors

ABSTRACT

Described herein are heteroaryl compounds that are antagonists of PGD 2  receptors. Also described are pharmaceutical compositions and medicaments that include the heteroaryl compounds described. Also described herein are methods of using such antagonists of PGD 2  receptors, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other PGD2-dependent or PGD2-mediated conditions or diseases.

RELATED APPLICATIONS

This application claims the benefit of U.S. provisional patentapplication No. 61/115,259 entitled “HETEROCYCLIC ANTAGONISTS OFPROSTAGLANDIN D₂ RECEPTORS” filed on Nov. 17, 2008, which isincorporated by reference in its entirety.

FIELD OF THE INVENTION

Described herein are compounds, methods of making such compounds,pharmaceutical compositions and medicaments comprising such compounds,and methods of using such compounds to treat, prevent or diagnosediseases, disorders or conditions associated with prostaglandin D₂.

BACKGROUND OF THE INVENTION

Prostaglandins are acidic lipids derived from the metabolism ofarachidonic acid by the action of cyclooxygenase enzymes and downstreamsynthases. Prostaglandins have a diverse range of activities and have awell recognized role in pain and inflammation.

Prostaglandin D₂ (PGD₂) is an acidic lipid mediator derived from themetabolism of arachidonic acid by cyclooxygenases and PGD₂ synthases.PGD₂ is produced by mast cells, macrophages and Th2 lymphocytes inresponse to local tissue damage as well as allergic inflammation indiseases such as asthma, rhinitis, and atopic dermatitis. Exogenous PGD₂applied to bronchial airways elucidates many characteristics of anasthmatic response suggesting that PGD₂ plays an importantpro-inflammatory role in allergic diseases.

PGD₂ binds to a number of receptors, which include the thromboxane-typeprostanoid (TP) receptor, PGD₂ receptor (DP, also known as DP₁) andchemoattractant receptor-homologous molecule expressed on Th2 cells(CRTH2; also known as DP₂). DP₂ is associated with promoting chemotaxisand activation of Th2 lymphocytes, eosinophils and basophils. Inparticular, PGD₂ binds to DP₂, and mediates its effects through aG_(i)-dependant elevation in calcium levels and reduction ofintracellular cyclic AMP. In Th2 lymphocytes, IL4, IL5 and IL13 cytokineproduction is stimulated. These cytokines have been implicated innumerous biological actions including, by way of example only,immunoglobulin E production, airway response, mucous secretion, andeosinophil recruitment.

SUMMARY OF THE INVENTION

Presented herein are compounds, pharmaceutical compositions andmedicaments, methods, for (a) diagnosing, preventing, or treatingallergic and non-allergic inflammation, (b) mitigating adverse signs andsymptoms that are associated with inflammation, and/or (c) controllingimmunological, or proliferative disorders. These disorders may arisefrom one or more of a genetic, iatrogenic, immunological, infectious,oncological, toxic, surgical, and/or traumatic etiology. In one aspect,the methods, compounds, pharmaceutical compositions, and medicamentsdescribed herein comprise antagonists of PGD₂ receptors. In one aspect,the methods, compounds, pharmaceutical compositions, and medicamentsdescribed herein comprise antagonists of DP₂

In one aspect provided herein are compounds of Formula (I),pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs,N-oxides, metabolites, and pharmaceutically acceptable solvates thereof,which are anatgonists of DP₂, and are used to treat patients sufferingfrom one or more PGD₂-dependent conditions or diseases, including, butnot limited to, asthma, rhinitis, chronic obstructive pulmonary disease,pulmonary hypertension, interstitial lung fibrosis, arthritis, allergy,psoriasis, inflammatory bowel disease, adult respiratory distresssyndrome, myocardial infarction, aneurysm, stroke, cancer, woundhealing, endotoxic shock, pain, proliferative disorders, inflammatoryconditions, eosinophilic esophagitis, eosinophil-associatedgastrointestinal disorders (EGID), idiopathic hypereosinophilicsyndrome, otitis, airway constriction, mucus secretion, nasalcongestion, increased microvascular permeability and recruitment ofeosinophils, urticaria, sinusitis, angioedema, anaphylaxia, chroniccough and Churg Strauss syndrome. In some embodiments, PGD₂-dependentconditions or diseases include those wherein an absolute or relativeexcess of PGD₂ is present and/or observed.

In one aspect are compounds having a linker-coupled diaryl moiety, inwhich one aryl moiety is a heteroaryl moiety and the other aryl moietyis a phenyl moiety, and in which the linker connects the two arylmoieties by a single atom, provided that this linking atom is optionallysubstituted if permitted by standard substitution rules; the phenylmoiety is further substituted at a position ortho to the linker group,and the heteroaryl moiety is further substituted at a position meta tothe linker group.

In one aspect is a compound having the structure of Formula (I),pharmaceutically acceptable salt, pharmaceutically acceptable solvate,N-oxide, or prodrug thereof:

-   -   wherein,    -   ring A is a substituted or unsubstituted heteroarylene, where        the X group and —C(R¹)₂Q group are on non-adjacent atoms of ring        A, wherein if ring A is substituted, then each substituent on        ring A is independently selected from H and R^(A);    -   Q is —C(═O)-Q¹, tetrazolyl, or a carboxylic acid bioisostere;        -   Q¹ is —OR¹⁵, —NHSO₂R⁹, —N(R¹⁰)₂, —NH—OH, or —NH—CN;    -   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —NR¹³—, —C(R¹⁶)₂—, or —C(═O)—;    -   each R¹ is independently selected from H, halogen, C₁-C₄alkyl,        and C₁-C₄haloalkyl;    -   each of R², R³, R⁴ and R⁵ is independently selected from H,        halogen, —CN, —NO₂, —OH, —OR¹⁰, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹,        —N(R¹⁰)S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰,        —OCO₂R¹⁰, —N(R¹⁰)₂, —NHCH₂CO₂R¹⁰, —OCH₂CO₂R¹⁰, —SCH₂CO₂R¹⁰,        —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂, —NR¹⁰C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R⁹,        —NR¹⁰—C₁-C₄alkylene-C(═O)R⁹, —NR¹⁰C(═O)OR⁹, C₁-C₆alkyl,        C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy,        C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, and        a substituted or unsubstituted heteroaryl;    -   each R^(A) is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR¹⁰, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹, —N(R¹⁰)S(═O)₂R⁹,        —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —OCO₂R¹⁰,        —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂, —NR¹⁰C(═O)N(R¹⁰)₂,        —NR¹⁰C(═O)R⁹, —NR¹⁰C(═O)OR⁹, C₁-C₆alkyl, C₁-C₆-fluoroalkyl,        C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, a substituted        or unsubstituted C₃-C₁₀cycloalkyl, and a substituted or        unsubstituted C₂-C₁₀heterocycloalkyl;    -   each R⁶ is H;    -   Z is —N—R⁷—, —S—, —S(═O)—, —S(═O)₂— or —O—;    -   R⁷ is —C(═O)R¹¹, —C(═O)OR¹², —C(═O)N(R¹³)₂, —S(═O)₂N(R¹³)₂ or        —S(═O)₂R¹²;        -   R¹¹ is C₁-C₆alkyl, C₁-C₆-fluoroalkyl, C₁-C₆heteroalkyl, a            substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted            or unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted            heteroaryl, —C₁-C₆alkylene-(substituted or unsubstituted            C₃-C₁₀cycloalkyl), —C₁-C₆alkylene-(substituted or            unsubstituted C₂-C₁₀heterocycloalkyl),            —C₁-C₆alkylene-(substituted or unsubstituted aryl) or            —C₁-C₆alkylene-(substituted or unsubstituted heteroaryl); or        -   R¹¹ is -L³-X³-Q³;            -   L³ is a —C₁-C₆alkylene-;            -   X³ is a bond, —O—, —S—, —S(═O)—, —S(═O)₂—, or —NR¹³—;            -   Q³ is a C₁-C₆alkyl, C₁-C₆-fluoroalkyl a substituted or                unsubstituted C₃-C₁₀cycloalkyl, a substituted or                unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or                unsubstituted aryl, a substituted or unsubstituted                heteroaryl, —C₁-C₆alkylene-(substituted or unsubstituted                C₃-C₁₀cycloalkyl), —C₁-C₆alkylene-(substituted or                unsubstituted C₂-C₁₀heterocycloalkyl),                —C₁-C₆alkylene-(substituted or unsubstituted aryl), or                C₁-C₆alkylene-(substituted or unsubstituted heteroaryl);        -   R¹² is C₁-C₆alkyl, C₁-C₆-fluoroalkyl, C₁-C₆heteroalkyl, a            substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted            or unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted            heteroaryl, —C₁-C₆alkylene-(substituted or unsubstituted            C₃-C₁₀cycloalkyl), —C₁-C₆alkylene-(substituted or            unsubstituted C₂-C₁₀heterocycloalkyl),            —C₁-C₆alkylene-(substituted or unsubstituted aryl) or            —C₁-C₆alkylene-(substituted or unsubstituted heteroaryl);        -   each R¹³ is independently H, —CN, C₁-C₆alkyl,            C₁-C₆-fluoroalkyl, C₁-C₆heteroalkyl, a substituted or            unsubstituted C₃-C₁₀cycloalkyl, a substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted            heteroaryl, —C₁-C₆alkylene-(substituted or unsubstituted            C₃-C₁₀cycloalkyl), —C₁-C₆alkylene-(substituted or            unsubstituted C₂-C₁₀heterocycloalkyl),            —C₁-C₆alkylene-(substituted or unsubstituted aryl) or            —C₁-C₆alkylene-(substituted or unsubstituted heteroaryl); or        -   two R¹³ groups attached to the same N atom are taken            together with the N atom to which they are attached to form            a substituted or unsubstituted heterocycle;    -   R⁸ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl, a        substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or        unsubstituted aryl, or a substituted or unsubstituted        heteroaryl, C₁-C₆alkylene-R¹⁴, —C₁-C₆alkylene-O—R¹⁴,        —C₁-C₆alkylene-S—R¹⁴, —C₁-C₆alkylene-S(═O)—R¹⁴,        —C₁-C₆alkylene-S(═O)₂—R¹⁴, —C₁-C₆alkylene-N(R¹⁴)₂,        —C₁-C₆alkylene-C(═O)—R¹⁴, —C₁-C₆alkylene-C(═O)O—R¹⁴—,        —C₁-C₆alkylene-OC(═O)—R¹⁴, —C₁-C₆alkylene-NR¹⁴C(═O)—R¹⁴ or        —C₁-C₆alkylene-C(═O)N(R¹⁴)₂;        -   each R¹⁴ is independently selected from H, C₁-C₆alkyl,            C₁-C₆heteroalkyl, C₁-C₆haloalkyl, a substituted or            unsubstituted C₃-C₁₀cycloalkyl, a substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted benzyl, a            substituted or unsubstituted naphthyl, or a substituted or            unsubstituted heteroaryl; or        -   two R¹⁴ groups attached to the same nitrogen are taken            together with the nitrogen atom to which they are attached            to form a substituted or unsubstituted heterocycle; or    -   R⁷ and R⁸ are taken together with the N atom to which they are        attached to form a substituted or unsubstituted heterocycle;    -   R⁹ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆-fluoroalkyl, a        substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or        unsubstituted aryl, a substituted or unsubstituted heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted aryl), or —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl);    -   each R¹⁰ is independently selected from H, C₁-C₆alkyl,        C₁-C₆heteroalkyl, C₁-C₆-fluoroalkyl, a substituted or        unsubstituted C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted aryl), and —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl); or    -   two R¹⁰ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted heterocycle;    -   R¹⁵ is selected from H and C₁-C₆alkyl; and    -   each R¹⁶ is independently selected from H, —OH, halogen, —CN,        C₁-C₆alkyl.

For any and all of the embodiments, substituents can be selected fromamong from a subset of the listed alternatives. For example. In someembodiments, Q is —C(═O)-Q¹ or tetrazolyl. In some embodiments, Q¹ is—OR¹⁵. In some embodiments, R¹⁵ is H, —CH₃, or —CH₂CH₃. In otherembodiments, R¹⁵ is H.

In some embodiments, Q is —CO₂H, —CO₂CH₃, or CO₂CH₂CH₃. In otherembodiments, Q is —CO₂H.

In some embodiments, each R¹ is independently selected from H, F, andC₁-C₄alkyl. In some embodiments, each R¹ is independently selected fromH, F, and —CH₃. In some embodiments, each R¹ is independently selectedfrom H and —CH₃. In some embodiments, each R¹ is H.

In some embodiments, the groups

are on non-adjacent atoms of ring A. In some embodiments, theaforementioned groups are in a meta relationship with respect to eachother on ring A (i.e. a 1,3 relationship with respect to each other onring A).

In some embodiments, ring A is a substituted or unsubstitutedheteroarylene, where X and —C(R¹)₂Q are on non-adjacent atoms of ring Ain a 1,3-relationship, wherein if ring A is substituted, then eachsubstituent on ring A is independently selected from H and R^(A).

In some embodiments, ring A is a substituted or unsubstitutedheteroarylene, where X and —C(R¹)₂Q are on non-adjacent atoms of ring Ain a 1,4-relationship, wherein if ring A is substituted, then eachsubstituent on ring A is independently selected from H and R^(A).

In some embodiments, X is —O—, —S—, or —C(R¹⁶)₂—. In some otherembodiments, X is —O— or —C(R¹⁶)₂—. In other embodiments, X is—C(CH₃)H—, —C(CH₃)₂—, or —CH₂—. In some embodiments, X is —CH₂—. In someother embodiments, X is —O—.

In some embodiments, each of R², R³, and R⁵ is independently selectedfrom H, halogen, —CN, —NO₂, —OH, —OR¹⁰, —S(═O)₂R⁹, —N(R¹⁰)S(═O)₂R⁹,—S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —OCO₂R¹⁰, —N(R¹⁰)₂,—C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂, —NR¹⁰C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R⁹,—NR¹⁰C(═O)OR⁹, C₁-C₆alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy,C₁-C₆alkoxy, and C₁-C₆heteroalkyl.

In some embodiments, each of R², R³, and R⁵ is independently selectedfrom H, halogen, —CN, —NO₂, —OH, —OR¹⁰, —N(R¹⁰)₂, C₁-C₆alkyl,C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, andC₁-C₆heteroalkyl.

In other embodiments, at least one of R², R³, and R⁵ are H. In someother embodiments, at least two of R², R³, and R⁵ are H. In someembodiments, each of R², R³, and R⁵ is H.

In some embodiments, Q is —C(═O)-Q¹ or tetrazolyl; Q¹ is —OR¹⁵; each R¹is independently selected from H, F, and —CH₃; each of R², R³, and R⁵ isindependently selected from H, halogen, —CN, —NO₂, —OH, —OR¹⁰, —N(R¹⁰)₂,C₁-C₄alkyl, C₁-C₄-fluoroalkyl, C₁-C₄-fluoroalkoxy, C₁-C₄alkoxy, andC₁-C₄heteroalkyl; X is —O—, —S—, or —C(R¹⁶)₂—; each R¹⁶ is independentlyselected from H and —CH₃.

In some embodiments, Q is —CO₂H, —CO₂CH₃, or —CO₂CH₂CH₃; X is —O—; eachR¹ is H; at least one of R², R³, and R⁵ are H.

In some embodiments, Q is —CO₂H, CO₂CH₃, or —CO₂CH₂CH₃; X is —CH₂—; eachR¹ is H; at least one of R², R³, and R⁵ are H.

In some embodiments, the compound of Formula (I) has a structureselected from:

In some embodiments, R¹⁵ is H, —CH₃, or —CH₂CH₃. In other embodiments,R¹⁵ is H.

In some embodiments, each R¹ is H; R¹⁵ is H; ring A is a substituted orunsubstituted heteroarylene selected from pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, triazinyl, thienyl, furanyl, pyrrolyl,thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl,isothiazolyl, triazolyl, tetrazolyl, wherein if ring A is substituted,then each substituent on ring A is independently selected from H andR^(A).

In some embodiments, ring A is a substituted or unsubstituted monocyclicheteroarylene, where ring A contains 0-1 oxygen atoms; 0-1 sulfur atoms;and 0-4 nitrogen atoms, wherein if ring A is substituted, then eachsubstituent on ring A is independently selected from H and R^(A).

In other embodiments, ring A is a substituted or unsubstitutedheteroarylene selected from pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl,isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isothiazolyl, triazolyl,tetrazolyl, wherein if ring A is substituted, then each substituent onring A is independently selected from H and R^(A).

In some other embodiments, ring A is a substituted or unsubstitutedmonocyclic heteroarylene ring, where ring A contains 0-1 oxygen atoms;0-1 sulfur atoms; and 1-4 nitrogen atoms, wherein if ring A issubstituted, then each substituent on ring A is independently selectedfrom H and R^(A).

In yet other embodiments, ring A is a substituted or unsubstituted5-membered monocyclic heteroarylene, where ring A contains 0-1 oxygenatoms; 0-1 sulfur atoms; and 1-4 nitrogen atoms, wherein if ring A issubstituted, then each substituent on ring A is independently selectedfrom H and R^(A).

In some embodiments, ring A is a substituted or unsubstitutedheteroarylene selected from pyrrolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, imidazolyl, pyrazolyl, isothiazolyl, triazolyl, andtetrazolyl, wherein if ring A is substituted, then each substituent onring A is independently selected from H and R^(A).

In some embodiments, ring A is a substituted or unsubstituted 6-memberedmonocyclic heteroarylene ring, where ring A contains 1-3 nitrogen atoms,wherein if ring A is substituted, then each substituent on ring A isindependently selected from H and R^(A). In some embodiments, ring A isa substituted or unsubstituted 6-membered monocyclic heteroarylene ring,where ring A contains 1 or 2 nitrogen atoms, wherein if ring A issubstituted, then each substituent on ring A is independently selectedfrom H and R^(A).

In some other embodiments, ring A is a substituted or unsubstitutedheteroarylene selected from pyridinyl, pyrimidinyl, pyridazinyl, andpyrazinyl, wherein if ring A is substituted, then each substituent onring A is independently selected from H and R^(A).

In one aspect, at least one R^(A) is H if ring A is substituted. In someembodiments, ring A is unsubstituted.

In some embodiments, each R^(A) is independently selected from H,halogen, —CN, —NO₂, —OH, —OR¹⁰, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹, —N(R¹⁰)₂R⁹,—S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —N(R¹⁰)₂, C₁-C₆alkyl, C₁-C₆-fluoroalkyl,C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, a substituted orunsubstituted C₃-C₆cycloalkyl, and a substituted or unsubstitutedC₂-C₆heterocycloalkyl; R⁴ is selected from halogen, —CN, —NO₂, —OH,—OR¹⁰, —S(═O)₂R⁹, —NHS(═O)₂R⁹, —N(C₁-C₆alkyl)S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,—C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —OCO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,—OC(═O)N(R¹⁰)₂, —NHC(═O)N(R¹⁰)₂, —N(C₁-C₄alkyl)C(═O)N(R¹⁰)₂, —NHC(═O)R⁹,—N(C₁-C₄alkyl)C(═O)R⁹, —NH—C₁-C₄alkylene-C(═O)R⁹, —NHC(═O)OR⁹,—N(C₁-C₄alkyl)C(═O)OR⁹, C₁-C₆alkyl, C₁-C₆-fluoroalkyl,C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, a substituted orunsubstituted C₃-C₆cycloalkyl, a substituted or unsubstitutedC₂-C₆heterocycloalkyl, a substituted or unsubstituted phenyl, and asubstituted or unsubstituted monocyclic heteroaryl.

In some embodiments, R⁹ is C₁-C₆alkyl, C₁-C₆-fluoroalkyl,C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, a substituted orunsubstituted monocyclic heteroaryl, —C₁-C₂alkylene-C₃-C₆cycloalkyl,—C₁-C₂alkylene-(substituted or unsubstituted phenyl), or—C₁-C₄alkylene-(substituted or unsubstituted monocyclic heteroaryl);each R¹⁰ is independently selected from H, C₁-C₆alkyl,C₁-C₆-fluoroalkyl, C₃-C₆cycloalkyl, a substituted or unsubstitutedphenyl, a substituted or unsubstituted monocyclic heteroaryl,—C₁-C₂alkylene-(C₃-C₆cycloalkyl), —C₁-C₂alkylene-(substituted orunsubstituted phenyl), and —C₁-C₂alkylene-(substituted or unsubstitutedheteroaryl).

In some embodiments, each R^(A) is each independently H, halogen, —CN,—OH, —OR¹⁰, —N(R¹⁰)₂, C₁-C₄alkyl, C₁-C₄-fluoroalkyl, C₁-C₄-fluoroalkoxy,C₁-C₄alkoxy, or C₁-C₄heteroalkyl.

In some embodiments, R⁴ is selected from halogen, —CN, —NO₂, —OH,—S(═O)₂R⁹, —NHS(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰,—OCO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂, —NHC(═O)N(R¹⁰)₂,—NHC(═O)R⁹, —NH—C₁-C₄alkylene-C(═O)R⁹, —NHC(═O)OR⁹, C₁-C₆alkyl,C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, asubstituted or unsubstituted C₃-C₆cycloalkyl, a substituted orunsubstituted C₂-C₆heterocycloalkyl, a substituted or unsubstitutedphenyl, and a substituted or unsubstituted monocyclic heteroaryl.

In some embodiments, each R^(A) is each independently H, halogen, —CN,—OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —OCH₃, —CH₃, —CF₃, or —OCF₃. In someembodiments, each R^(A) is each independently H, halogen, —CN, —OH,—OCH₃, —CH₃, —CF₃, or —OCF₃.

In some embodiments, R⁴ is selected from —NHS(═O)₂R⁹, —N(R¹⁰)₂,—NHC(═O)N(R¹⁰)₂, —NHC(═O)R⁹, and —NHC(═O)OR⁹. In some embodiments, R⁴ isselected from —NHS(═O)₂R⁹ or —NHC(═O)R⁹. In some embodiments, R⁴ is—NHC(═O)R⁹.

In some embodiments, R⁴ is selected from a substituted or unsubstitutedC₃-C₆cycloalkyl, a substituted or unsubstituted C₂-C₆heterocycloalkyl, asubstituted or unsubstituted phenyl, a substituted or unsubstitutednaphthyl, a substituted or unsubstituted bicyclic heteroaryl and asubstituted or unsubstituted monocyclic heteroaryl. In some embodiments,R⁴ is selected from a C₃-C₆cycloalkyl, a substituted or unsubstitutedC₂-C₆heterocycloalkyl, a substituted or unsubstituted phenyl, and asubstituted or unsubstituted monocyclic heteroaryl. In some embodiments,R⁴ is selected from a C₃-C₆cycloalkyl, a substituted or unsubstitutedC₂-C₆heterocycloalkyl, a substituted or unsubstituted phenyl, and asubstituted or unsubstituted monocyclic C₁-C₅heteroaryl.

In some embodiments, R⁴ is selected from halogen, —CN, —OH, —S(═O)₂R⁹,—NHS(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂,—C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂, —NHC(═O)N(R¹⁰)₂, —NHC(═O)R⁹, C₁-C₆alkyl,C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, and C₁-C₆alkoxy.

In some embodiments, R⁴ is selected from halogen, —NHS(═O)₂R⁹,—S(═O)₂NHR¹⁰, —NHC(═O)R⁹, —C(═O)NHR¹⁰, —NHC(═O)NHR¹⁰, —NHC(═O)OR⁹,C₁-C₄alkyl, C₁-C₄-fluoroalkyl, C₁-C₄-fluoroalkoxy, and C₁-C₄alkoxy.

In some embodiments, Z is —S—, —S(═O)—, —S(═O)₂— or —O—. In someembodiments, Z is —O—. In some embodiments, Z is —S—, —S(═O)—, or—S(═O)₂—. In some embodiments, Z is —S—.

In some embodiments, Z is —S—, —S(═O)—, or —S(═O)₂—; R⁸ is C₁-C₆alkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl, a substituted orunsubstituted phenyl, a substituted or unsubstituted monocyclicheteroaryl, C₁-C₄alkylene-R¹⁴, —C₁-C₄alkylene-O R¹⁴,—C₁-C₄alkylene-N(R¹⁴)₂₅—C₁-C₄alkylene-C(═O)—R¹⁴,—C₁-C₄alkylene-C(═O)O—R¹⁴—, or —C₁-C₄alkylene-C(═O)N(R¹⁴)₂; each R¹⁴ isindependently selected from H, C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, a substituted or unsubstituted C₃-C₆cycloalkyl, asubstituted or unsubstituted phenyl, a substituted or unsubstitutedbenzyl, a substituted or unsubstituted naphthyl, or a substituted orunsubstituted monocyclic heteroaryl; or two R¹⁴ groups attached to thesame nitrogen are taken together with the nitrogen atom to which theyare attached to form a substituted or unsubstitutedC₃-C₆heterocycloalkyl.

In some embodiments, R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,a substituted or unsubstituted phenyl, a substituted or unsubstitutedmonocyclic heteroaryl, or —C₁-C₄alkylene-R¹⁴; R¹⁴ is C₆cycloalkyl, asubstituted or unsubstituted phenyl, or a substituted or unsubstitutedmonocyclic heteroaryl.

In some embodiments, Z is —S—; R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl,C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, a substituted orunsubstituted monocyclic heteroaryl, or —C₁-C₄alkylene-R¹⁴; R¹⁴ isC₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, or a substitutedor unsubstituted monocyclic heteroaryl.

In some embodiments, Z is —N—R⁷; R⁷ is —C(═O)R¹¹, —C(═O)OR¹², or—C(═OO)N(R¹³)₂. In some embodiments, R⁷ is —C(═O)R¹¹. In someembodiments, R⁷ is —C(═O)OR¹². In some embodiments, R⁷ is—C(═OO)N(R¹³)₂.

In some embodiments, Z is —N—R⁷; R⁷ is —C(═O)R¹¹, —C(═O)OR¹², or—C(═O)N(R¹³)₂; R¹¹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl,C₃-C₆cycloalkyl, a substituted or unsubstituted aryl, a substituted orunsubstituted heteroaryl, —C₁-C₄alkylene-(C₃-C₆cycloalkyl),—C₁-C₄alkylene-(substituted or unsubstituted phenyl) or—C₁-C₄alkylene-(substituted or unsubstituted monocyclic heteroaryl); orR¹¹ is -L³-X³-Q³; L³ is a —C₁-C₄alkylene-; X³ is a bond, —O—, —S—,—S(═O)—, or —S(═O)₂—; Q³ is a C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, a substituted orunsubstituted monocyclci heteroaryl, —C₁-C₄alkylene-(C₃-C₁₀cycloalkyl),—C₁-C₄alkylene-(substituted or unsubstituted phenyl), orC₁-C₄alkylene-(substituted or unsubstituted monocyclic heteroaryl); R¹²is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, asubstituted or unsubstituted phenyl, a substituted or unsubstitutedmonocyclic heteroaryl, —C₁-C₄alkylene-(C₃-C₆cycloalkyl),—C₁-C₄alkylene-(substituted or unsubstituted phenyl) or—C₁-C₄alkylene-(substituted or unsubstituted monocyclic heteroaryl);each R¹³ is independently H, —CN, C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, a substituted or unsubstitutedphenyl, a substituted or unsubstituted monocyclic heteroaryl,—C₁-C₄alkylene-(C₃-C₆cycloalkyl), —C₁-C₄alkylene-(substituted orunsubstituted phenyl) or —C₁-C₄alkylene-(substituted or unsubstitutedmonocyclic heteroaryl); or two R¹³ groups attached to the same N atomare taken together with the N atom to which they are attached to form asubstituted or unsubstituted monocyclic heterocycle; R⁸ is C₁-C₆alkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, a substituted or unsubstitutedC₃-C₁₀cycloalkyl, a substituted or unsubstituted phenyl, or asubstituted or unsubstituted monocyclic heteroaryl, or—C₁-C₄alkylene-R¹⁴; R¹⁴ is C₃-C₆cycloalkyl, a substituted orunsubstituted phenyl, a substituted or unsubstituted naphthyl, asubstituted or unsubstituted monocyclic heteroaryl or a substituted orunsubstituted bicyclic heteroaryl.

In some embodiments, Z is —N—R⁷; R⁷ is —C(═O)R¹¹; R¹¹ is C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₃-C₆cycloalkyl, a substituted or unsubstitutedphenyl, a substituted or unsubstituted monocyclic heteroaryl,—C₁-C₂alkylene-(C₃-C₆cycloalkyl), —C₁-C₂alkylene-(substituted orunsubstituted phenyl) or —C₁-C₂alkylene-(substituted or unsubstitutedmonocyclic heteroaryl); or R¹¹ is -L³-X³-Q³; L³ is a —C₁-C₄alkylene-; X³is a bond, —O—, —S—, —S(═O)—, or —S(═O)₂—; Q³ is a C₁-C₆alkyl, asubstituted or unsubstituted phenyl, a substituted or unsubstitutedmonocyclic heteroaryl, —C₁-C₄alkylene-(substituted or unsubstitutedphenyl), or C₁-C₄alkylene-(substituted or unsubstituted monocyclicheteroaryl).

In some embodiments, R¹¹ is C₁-C₆alkyl, C₃-C₆cycloalkyl, a substitutedor unsubstituted phenyl, a substituted or unsubstituted monocyclicheteroaryl, —C₁-C₂alkylene-(substituted or unsubstituted phenyl) or—C₁-C₂alkylene-(substituted or unsubstituted monocyclic heteroaryl); orR¹¹ is -L³-X³-Q³; L³ is a —C₁-C₄alkylene-; X³ is a bond, —O—, —S—,—S(═O)—, or —S(═O)₂—; Q³ is a C₁-C₆alkyl, a substituted or unsubstitutedphenyl, a substituted or unsubstituted monocyclic heteroaryl,—C₁-C₄alkylene-(substituted or unsubstituted phenyl), orC₁-C₄alkylene-(substituted or unsubstituted monocyclic heteroaryl); R⁸is C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl, a substituted orunsubstituted phenyl, a substituted or unsubstituted monocyclicheteroaryl, or —C₁-C₂alkylene-R¹⁴; R¹⁴ is a substituted or unsubstitutedphenyl, or a substituted or unsubstituted monocyclic heteroaryl.

In some embodiments, R¹¹ is C₁-C₆alkyl, C₃-C₆cycloalkyl,—C₁-C₂alkylene-(substituted or unsubstituted phenyl) or—C₁-C₂alkylene-(substituted or unsubstituted monocyclic heteroaryl); orR¹¹ is -L³-X³-Q³; L³ is a —C₁-C₄alkylene-; X³ is a bond, —O—, —S—,—S(═O)—, or —S(═O)₂—; Q³ is a C₁-C₆alkyl, a substituted or unsubstitutedphenyl, or —C₁-C₄alkylene-(substituted or unsubstituted phenyl); R⁸ isC₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl, or —C₁-C₂alkylene-R¹⁴; R¹⁴is a substituted or unsubstituted phenyl, or a substituted orunsubstituted monocyclic heteroaryl. In some embodiments, R¹¹ isC₁-C₆alkyl or C₃-C₆cycloalkyl.

In some embodiments, Z is —N—R⁷; R⁷ is —C(═O)OR¹²; R¹² is C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₃-C₆cycloalkyl, a substituted or unsubstitutedphenyl, a substituted or unsubstituted monocyclic heteroaryl,—C₁-C₂alkylene-(C₃-C₆cycloalkyl), —C₁-C₂alkylene-(substituted orunsubstituted phenyl) or —C₁-C₂alkylene-(substituted or unsubstitutedmonocyclic heteroaryl); R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl,C₃-C₆cycloalkyl, or —C₁-C₂alkylene-R¹⁴; R¹⁴ is C₃-C₆cycloalkyl, asubstituted or unsubstituted phenyl, or a substituted or unsubstitutedmonocyclic heteroaryl.

In some embodiments, R¹² is C₁-C₆alkyl, —C₁-C₂alkylene-(substituted orunsubstituted phenyl) or —C₁-C₂alkylene-(substituted or unsubstitutedmonocyclic heteroaryl); R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl, orC₃-C₆cycloalkyl. In some embodiments, R¹² is C₁-C₆alkyl or—C₁-C₂alkylene-(substituted or unsubstituted phenyl).

In some embodiments, Z is —N—R⁷; R⁷ is —C(═OO)N(R¹³)₂; each R¹³ isindependently H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₃-C₆cycloalkyl, asubstituted or unsubstituted phenyl, a substituted or unsubstitutedmonocyclic heteroaryl, —C₁-C₂alkylene-(C₃-C₆cycloalkyl),—C₁-C₂alkylene-(substituted or unsubstituted phenyl) or—C₁-C₂alkylene-(substituted or unsubstituted monocyclic heteroaryl); R⁸is C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl, a substituted orunsubstituted phenyl, or a substituted or unsubstituted monocyclicheteroaryl, or —C₁-C₂alkylene-R¹⁴; R¹⁴ is C₃-C₆cycloalkyl, a substitutedor unsubstituted phenyl, or a substituted or unsubstituted monocyclicheteroaryl.

In some embodiments, one R¹³ is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, a substituted orunsubstituted monocyclic heteroaryl, —C₁-C₂alkylene-(C₃-C₆cycloalkyl),—C₁-C₂alkylene-(substituted or unsubstituted phenyl) or—C₁-C₂alkylene-(substituted or unsubstituted monocyclic heteroaryl) andthe other R¹³ is H or C₁-C₄alkyl; R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl,C₃-C₆cycloalkyl, or —C₁-C₂alkylene-R¹⁴; R¹⁴ is a substituted orunsubstituted phenyl or a substituted or unsubstituted monocyclicheteroaryl.

In some embodiments, one R¹³ is C₁-C₆alkyl, —C₁-C₂alkylene-(substitutedor unsubstituted phenyl) or —C₁-C₂alkylene-(substituted or unsubstitutedmonocyclic heteroaryl) and the other R¹³ is H or C₁-C₄alkyl; R⁸ isC₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl, or —C₁-C₂alkylene-R¹⁴; R¹⁴is a substituted or unsubstituted phenyl. In some embodiments, one R¹³is —C₁-C₂alkylene-(substituted or unsubstituted phenyl) or—C₁-C₂alkylene-(substituted or unsubstituted monocyclic heteroaryl) andthe other R¹³ is H or C₁-C₄alkyl. In some embodiments, one R¹³ is—C₁-C₂alkylene-(substituted or unsubstituted phenyl) and the other R¹³is H or C₁-C₄alkyl.

In some embodiments, Z is —N—R⁷; and R⁷ and R⁸ are taken together withthe nitrogen atom to which they are attached to form a substituted orunsubstituted heterocycle.

In some embodiments, R⁸ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,a substituted or unsubstituted cycloalkyl, a substituted orunsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, ora substituted or unsubstituted heteroaryl, —C₁-C₆alkylene-R¹⁴,—C₁-C₆alkylene-O—R¹⁴, —C₁-C₆alkylene-N(R¹⁴)₂, —C₁-C₆alkylene-C(═O)—R¹⁴,—C₁-C₆alkylene-C(═O)O—R¹⁴—, or —C₁-C₆alkylene-C(═O)N(R¹⁴)₂; each R¹⁴ isindependently selected from H, C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, a substituted or unsubstituted cycloalkyl, a substitutedor unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl,a substituted or unsubstituted benzyl, a substituted or unsubstitutednaphthyl, or a substituted or unsubstituted heteroaryl; or two R¹⁴groups attached to the same nitrogen are taken together with thenitrogen atom to which they are attached to form a substituted orunsubstituted C₃-C₆heterocycloalkyl

In some other embodiments, R⁸ is C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, a substituted or unsubstituted cycloalkyl, a substitutedor unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl,or a substituted or unsubstituted heteroaryl, —C₁-C₆alkylene-R¹⁴,—C₁-C₆alkylene-O—R¹⁴, —C₁-C₆alkylene-N(R¹⁴)₂,—C₁-C₆alkylene-C(═O)O—R¹⁴—, or —C₁-C₆alkylene-C(═O)N(R¹⁴)₂; each R¹⁴ isindependently selected from H, and C₁-C₆alkyl.

In other embodiments, R⁸ is C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, a substituted or unsubstituted cycloalkyl, a substitutedor unsubstituted aryl, a substituted or unsubstituted heteroaryl,C₁-C₆alkylene-R¹⁴, or —C₁-C₆alkylene-O—R¹⁴; R¹⁴ is selected from H,C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl, a substituted orunsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, a substituted orunsubstituted benzyl, and a substituted or unsubstituted heteroaryl.

In some other embodiments, R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆heteroalkyl, (a substituted or unsubstituted monocyclic or bicycliccycloalkyl) or —C₁-C₄alkylene-R¹⁴; R¹⁴ is a substituted or unsubstitutedaryl, or a substituted or unsubstituted heteroaryl. In some otherembodiments, R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl or—C₁-C₄alkylene-R¹⁴; R¹⁴ is a substituted or unsubstituted phenyl, or asubstituted or unsubstituted monocyclic C₁-C₅heteroaryl.

In some embodiments, R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl, orC₁-C₆heteroalkyl. In some embodiments, R⁸ is C₁-C₆alkyl orC₁-C₆haloalkyl.

In some embodiments, R⁸ is —C₁-C₄alkylene-R¹⁴; R¹⁴ is a substituted orunsubstituted aryl, or a substituted or unsubstituted heteroaryl. Insome embodiments, R⁸ is —C₁-C₂alkylene-R¹⁴. In some embodiments, R¹⁴ isa substituted or unsubstituted phenyl, or a substituted or unsubstitutedmonocyclic C₁-C₅heteroaryl.

In some embodiments, R⁸ is isopropyl, tert-butyl, —CH₂CF₃, —CH₂CO₂H,—CH₂CH₂N(CH₃)₂, phenyl, 4-chlorophenyl, benzyl, phenethyl, thiazol-2-yl,5-methyl-[1,3,4]thiadiazol-2-yl, pyridin-2-yl, or quinolin-2-yl.

Any combination of the groups described above for the various variablesis contemplated herein.

Compounds of Formula (I) are antagonists of DP₂. In specificembodiments, the antagonist of DP₂ is selective for DP₂. In otherembodiments, the antagonist of DP₂ is also an antagonist of DP₁. In someembodiments, the antagonist of DP₂ is also an antagonist of TP(thromboxane receptor).

In other embodiments, presented herein are compounds selected fromactive metabolites, solvates, pharmaceutically acceptable salts orpharmaceutically acceptable prodrugs of a compound of Formula (I).

In one aspect, provided herein is a pharmaceutical compositioncomprising a therapeutically effective amount of a compound providedherein. In some embodiments, the pharmaceutical composition alsocontains a pharmaceutically acceptable excipient.

In some embodiments, provided herein is a pharmaceutical compositioncomprising a therapeutically effective amount of a compound disclosedherein, or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable inactive ingredient selected frompharmaceutically acceptable diluents, pharmaceutically acceptableexcipients, and pharmaceutically acceptable carriers.

In some embodiments, (i) the pharmaceutical composition is formulatedfor intravenous injection, oral administration, buccal administration,inhalation, nasal administration, topical administration, ophthalmicadministration or otic administration; or

(ii) the pharmaceutical composition is a tablet, a pill, a capsule, aliquid, an inhalant, a nasal spray solution, a suppository, asuspension, a gel, a colloid, a dispersion, a suspension, a solution, anemulsion, an ointment, a lotion, an eye drop or an ear drop.

In some embodiments, the pharmaceutical composition further comprisesone or more additional therapeutically active agents selected from5-lipoxygenase-activating protein inhibitors, 5-lipoxygenase inhibitors,CYSLTR1 antagonists, CYSLTR2 antagonists, BLT1 antagonists, BLT2antagonists, thromboxane antagonists, DP1 receptor antagonists, DP1receptor agonists, IP receptor agonists, anti-IgE, chemokine receptorantagonists, IL5 antibody, bronchodilators, theophylline, leukotrienereceptor antagonists, leukotriene formation inhibitors, decongestants,antihistamines, mucolytics, corticosteroids, glucocorticoids,anticholinergics, antitussives, analgesics, expectorants, and β-2agonists.

In some embodiments, described herein is a method for treating aPGD₂-dependent condition or disease in a patient comprisingadministering to the patient a therapeutically effective amount of acompound described herein. In some embodiments, the PGD₂-dependentcondition or disease is selected from asthma, rhinitis, allergicconjuctivitis, atopic dermatitis, chronic obstructive pulmonary disease(COPD), pulmonary hypertension, interstitial lung fibrosis, arthritis,allergy, psoriasis, inflammatory bowel disease, adult respiratorydistress syndrome, myocardial infarction, aneurysm, stroke, cancer,wound healing, endotoxic shock, pain, inflammatory conditions,eosinophilic esophagitis, eosinophil-associated gastrointestinaldisorders (EGID), idiopathic hypereosinophilic syndrome, otitis, airwayconstriction, mucus secretion, nasal congestion, increased microvascularpermeability and recruitment of eosinophils, urticaria, sinusitis,angioedema, anaphylaxia, chronic cough and Churg Strauss syndrome. Insome embodiments, the PGD₂-dependent disease or condition is arespiratory disease or condition. In some embodiments, the respiratorydisease or condition is asthma, rhinitis or chronic obstructivepulmonary disease (COPD).

In some embodiments, the method further comprises administering to thepatient a second therapeutic agent selected from5-lipoxygenase-activating protein inhibitors, 5-lipoxygenase inhibitors,CYSLTR1 antagonists, CYSLTR2 antagonists, BLT1 antagonists, BLT2antagonists, thromboxane antagonists, DP1 receptor antagonists, DP1receptor agonists, IP receptor agonists, anti-IgE, chemokine receptorantagonists, IL5 antibody, bronchodilators, theophylline, leukotrienereceptor antagonists, leukotriene formation inhibitors, decongestants,antihistamines, mucolytics, corticosteroids, glucocorticoids,anticholinergics, antitussives, analgesics, expectorants, and β-2agonists.

In certain embodiments, presented herein are methods for treating aPGD₂-dependent condition or disease in a patient comprisingadministering to the patient a therapeutically effective amount of anantagonist of DP₂ having the structure of Formula (I).

In certain aspects, provided herein is a method for treatinginflammation in a mammal comprising administering a therapeuticallyeffective amount of a compound provided herein to the mammal in need.

In a specific aspect, provided herein is a method for treating asthma ina mammal comprising administering a therapeutically effective amount ofa compound provided herein to the mammal in need. In a further oralternative embodiment, provided herein is a method for treating asthmain a mammal comprising administering a therapeutically effective amountof a compound provided herein, such as, for example, a compound ofFormula (I), to the mammal in need.

In another aspect are compounds presented in Table 1 or 2. In anotheraspect are compounds presented in Table 1 or 2, or pharmaceuticallyacceptable salts, pharmaceutically active metabolites, pharmaceuticallyacceptable prodrugs, and pharmaceutically acceptable solvates thereof,which antagonize DP₂ and are used to treat patients suffering from oneor more PGD₂-dependent conditions or diseases, including, but notlimited to, asthma, rhinitis, chronic obstructive pulmonary disease,pulmonary hypertension, interstitial lung fibrosis, arthritis, allergy,psoriasis, inflammatory bowel disease, adult respiratory distresssyndrome, myocardial infarction, aneurysm, stroke, cancer, endotoxicshock, proliferative disorders and inflammatory conditions.

In one aspect, the compounds of Formula (I), including pharmaceuticallyacceptable salts, pharmaceutically acceptable prodrugs, andpharmaceutically acceptable solvates thereof, are antagonists of CRTH2.In various embodiments presented herein, these compounds are used totreat patients suffering from one or more PGD₂-dependent conditions ordiseases, including, but not limited to, asthma, rhinitis, chronicobstructive pulmonary disease, pulmonary hypertension, interstitial lungfibrosis, rhinitis, allergy, and adult respiratory distress syndrome.

In one aspect, the compounds of Formula (I) are antagonists of DP₂. Instill further or alternative embodiments such antagonists of DP₂ alsoantagonize other related PGD₂ receptors. Related PGD₂ receptors include,but are not limited to, DP₁ and TP.

In one aspect, the compounds of Formula (I) are administered with a TPantagonist. TP antagonists inhibit bronchoconstriction,vasoconstriction, and platelet aggregation. In one aspect,co-administration of a TP antagonist with a compound of Formula (I)inhibits bronchoconstrictor effects of PGD₂ and other prostanoids.

In further or alternative embodiments, the compounds of Formula (I) areincluded into pharmaceutical compositions or medicaments used fortreating a PGD₂-dependent or PGD₂ mediated condition or disease in apatient.

The pharmaceutical formulations described herein are administered to asubject by multiple administration routes, including but not limited to,oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical or transdermal administration routes. Thepharmaceutical formulations described herein include, but are notlimited to, aqueous liquid dispersions, self-emulsifying dispersions,solid solutions, liposomal dispersions, aerosols, solid dosage forms,powders, immediate release formulations, controlled releaseformulations, fast melt formulations, tablets, capsules, pills, delayedrelease formulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate andcontrolled release formulations.

In some embodiments, the compounds of Formula (I) are administeredorally.

In some embodiments, the compounds of Formula (I) are administeredtopically. In such embodiments, the compound of Formula (I) isformulated into a variety of topically administrable compositions, suchas solutions, suspensions, lotions, gels, pastes, medicated sticks,medicated bandages, shampoos, rubs, scrubs, smears, balms, creams orointments. Such pharmaceutical compounds optionally containsolubilizers, stabilizers, tonicity enhancing agents, buffers andpreservatives.

In another aspect, the compounds of Formula (I) are administered byintranasal administration.

In another aspect, the compounds of Formula (I) are formulated forintranasal administration. Such formulations include nasal sprays, nasalmists, nasal gels, and the like.

In another aspect, the compounds of Formula (I) are formulated as eyedrops.

In one aspect, the compounds of Formula (I) are administered topicallyto the skin.

In another aspect, compounds of Formula (I) are used to treat or preventinflammatory conditions. Inflammatory conditions include, but are notlimited to, asthma, rhinitis, chronic obstructive pulmonary disease,pulmonary hypertension, interstitial lung fibrosis, atherosclerosis,aortic aneurysm, myocardial infarction, and stroke.

In another aspect, compounds of Formula (I) are used to treat or preventimmunological disorders. In one aspect the immunological disordersinclude, but are not limited to, allergy or to excessive orinappropriate response to an endogenous or exogenous antigen. In certainembodiments, the immunological disorder that is characterized by immunedysregulation that is not accompanied by inflammation.

In another aspect, compounds of Formula (I) are used to treat or preventproliferative disorders. In one aspect the proliferative disordersinclude, but are not limited to, cancer and noncancerous disorders,including, but not limited to, those involving the skin or lymphatictissues.

In additional aspects, such conditions are iatrogenic and increases in,or abnormal localization of, PGD₂ is induced by other therapies ormedical or surgical procedures. In other embodiments, the PGD₂-dependentor PGD₂ mediated condition or disease is caused by surgery.

In other aspects, the methods, compounds, pharmaceutical compositions,and medicaments described herein are used to prevent the cellularactivity of PGD₂. In other aspects, such methods, compounds,pharmaceutical compositions, and medicaments comprise DP₂ antagonistsdisclosed herein for the treatment of asthma by modulating the activityof enzymes or proteins in a patient wherein such enzymes or proteins areinvolved in the PGD₂ pathway such as, by way of example, DP₂. In yetother aspects, the methods, compounds, pharmaceutical compositions, andmedicaments described herein are used in combination with other medicaltreatments or surgical modalities.

In one aspect are methods for reducing/antagonizing the PGD₂ activationof DP₂ in a mammal comprising administering to the mammal at least oncean effective amount of a compound having the structure of Formula (I).

In another aspect are methods for modulating, including reducing and/orantagonizing the activation of DP₂, directly or indirectly, in a mammalcomprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (I).

In another aspect, presented herein are methods for modulating,including reducing and/or antagonizing the activity of PGD₂ in a mammal,directly or indirectly, comprising administering to the mammal at leastonce an effective amount of at least one compound having the structureof Formula (I).

In another aspect are methods for treating PGD₂-dependent or PGD₂mediated conditions or diseases, comprising administering to the mammalat least once an effective amount of at least one compound having thestructure of Formula (I).

In another aspect are methods for treating inflammation comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (I).

In another aspect are methods for treating immunological abnormalitiescomprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (I).

In another aspect are methods for treating respiratory diseasescomprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (I). In afurther embodiment of this aspect, the respiratory disease is asthma. Ina further embodiment of this aspect, the respiratory disease includes,but is not limited to, adult respiratory distress syndrome and allergic(extrinsic) asthma, non-allergic (intrinsic) asthma, acute severeasthma, chronic asthma, clinical asthma, neutrophilic asthma, nocturnalasthma, allergen-induced asthma, aspirin-sensitive asthma,exercise-induced asthma, isocapnic hyperventilation, child-onset asthma,adult-onset asthma, cough-variant asthma, occupational asthma,steroid-resistant asthma, seasonal asthma.

In another aspect are methods for treating respiratory diseasescomprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (I). In afurther embodiment of this aspect, the respiratory disease is rhinitis.In a further embodiment of this aspect, the respiratory diseaseincludes, but is not limited to, allergic (extrinsic) rhinitis,non-allergic (intrinsic) rhinitis, chronic rhinitis, allergen-inducedrhinitis, aspirin-sensitive rhinitis, child-onset rhinitis, adult-onsetrhinitis, occupational rhinitis, steroid-resistant rhinitis, seasonalrhinitis, perennial rhinitis, rhinosinusitis, and rhinopolyposis.

In another aspect are methods for treating chronic obstructive pulmonarydisease comprising administering to the mammal at least once aneffective amount of at least one compound having the structure ofFormula (I). In a further embodiment of this aspect, chronic obstructivepulmonary disease includes, but is not limited to, chronic bronchitisand/or emphysema, pulmonary hypertension, interstitial lung fibrosisand/or airway inflammation and cystic fibrosis.

In another aspect are methods for preventing increased mucosal secretionand/or edema in a disease or condition comprising administering to themammal at least once an effective amount of at least one compound havingthe structure of Formula (I).

In another aspect are methods for treating vasoconstriction,atherosclerosis and its sequelae, myocardial ischemia, myocardialinfarction, aortic aneurysm, vasculitis, cardiac arrhythmia, and strokecomprising administering to the mammal an effective amount of a compoundhaving the structure of Formula (I).

In another aspect are methods for treating organ reperfusion injuryfollowing organ ischemia and/or endotoxic shock comprising administeringto the mammal at least once an effective amount of at least one compoundhaving the structure of Formula (I).

In another aspect are methods for reducing the constriction of bloodvessels in a mammal comprising administering to the mammal at least oncean effective amount of at least one compound having the structure ofFormula (I).

In another aspect are methods for lowering or preventing an increase inblood pressure of a mammal comprising administering to the mammal atleast once an effective amount of at least one compound having thestructure of Formula (I).

In another aspect are methods for preventing eosinophil and/or basophiland/or dendritic cell and/or neutrophil and/or monocyte or Th2 cellrecruitment comprising administering to the mammal at least once aneffective amount of at least one compound having the structure ofFormula (I).

A further aspect are methods for the prevention or treatment of abnormalbone remodeling, loss or gain, including diseases or conditions as, byway of example, osteopenia, osteoporosis, Paget's disease, cancer,trauma, surgery, and other diseases comprising administering to themammal at least once an effective amount of at least one compound havingthe structure of Formula (I).

In another aspect are methods for preventing ocular inflammation andallergic conjunctivitis, vernal keratoconjunctivitis, and papillaryconjunctivitis comprising administering to the mammal at least once aneffective amount of at least one having the structure of Formula (I).

In another aspect are methods for treating CNS disorders comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (I). CNS disordersinclude, but are not limited to, multiple sclerosis, Parkinson'sdisease, Alzheimer's or other degenerative disease, stroke, cerebralischemia, retinal ischemia, post-surgical cognitive dysfunction,migraine, peripheral neuropathy/neuropathic pain, spinal cord injury,cerebral edema and head injury.

In another aspect are methods for treating pain comprising administeringto the mammal at least once an effective amount of at least one compoundhaving the structure of Formula (I).

A further aspect are methods for the treatment of cancer comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (I). The type ofcancer includes, but is not limited to, pancreatic cancer and othersolid or hematological tumors.

In another aspect are methods for treating endotoxic shock and septicshock comprising administering to the mammal at least once an effectiveamount of at least one compound having the structure of Formula (I).

In another aspect are methods for treating rheumatoid arthritis andosteoarthritis comprising administering to the mammal at least once aneffective amount of at least one compound having the structure ofFormula (I).

In another aspect are methods for treating or preventing increasedgastrointestinal diseases comprising administering to the mammal atleast once an effective amount of at least one compound having thestructure of Formula (I). Such diseases include, by way of example only,chronic gastritis, eosinophilic gastroenteritis, and gastric motordysfunction.

A further aspect are methods for treating kidney diseases comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (I). Such diseasesinclude, by way of example only, acute tubular necrosis,glomerulonephritis, cyclosporine nephrotoxicity, renal ischemia, andreperfusion injury.

In another aspect are methods for preventing or treating acute orchronic renal insufficiency comprising administering to the mammal atleast once an effective amount of at least one compound having thestructure of Formula (I).

In another aspect are methods to diminish the inflammatory aspects ofacute infections within one or more solid organs or tissues such as thekidney with acute pyelonephritis.

In another aspect are methods for preventing or treating acute orchronic disorders involving recruitment or activation of eosinophilscomprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (I).

In another aspect are methods for preventing or treating acute orchronic erosive disease or motor dysfunction of the gastrointestinaltract caused by non-steroidal anti-inflammatory drugs (includingselective or non-selective cyclooxygenase-1 or -2 inhibitors) comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (I).

A further aspect are methods for the prevention or treatment ofrejection or dysfunction in a transplanted organ or tissue comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (I).

In another aspect are methods for treating inflammatory responses of theskin comprising administering to the mammal at least once an effectiveamount of at least one compound having the structure of Formula (I).Such inflammatory responses of the skin include, by way of example,dermatitis, contact dermatitis, eczema, urticaria, rosacea, andscarring. In another aspect are methods for reducing psoriatic lesionsin the skin, joints, or other tissues or organs, comprisingadministering to the mammal an effective amount of a first compoundhaving the structure of Formula (I).

A further aspect are methods for the treatment of cystitis, including,by way of example only, interstitial cystitis, comprising administeringto the mammal at least once an effective amount of at least one compoundhaving the structure of Formula (I).

A further aspect are methods for the treatment of Familial MediterraneanFever comprising administering to the mammal at least once an effectiveamount of at least one compound having the structure of Formula (I).

In a further aspect are methods to treat hepatorenal syndrome comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (I).

In a further aspect are methods to modulate the immune response toendogenous or exogenous antigens.

In a further aspect are methods to treat acute or chronic allergicresponses to exogenous substances that have been ingested such as foods(e.g., peanuts) or drugs (e.g., penicillin, non-steroidalanti-inflammatory drugs or the like).

In another aspect is the use of a compound of Formula (I) in themanufacture of a medicament for treating an inflammatory disease orcondition in an animal in which the activity of at least onePGD₂-associated protein contributes to the pathology and/or symptoms ofthe disease or condition. In one embodiment of this aspect, the PGD₂pathway protein is CRTH2. In another or further embodiment of thisaspect, the inflammatory disease or conditions are respiratory,cardiovascular, or proliferative diseases.

In any of the aforementioned aspects are further embodiments in which:(a) the effective amount of the compound is systemically administered tothe mammal; and/or (b) the effective amount of the compound isadministered orally to the mammal; and/or (c) the effective amount ofthe compound is intravenously administered to the mammal; and/or (d) theeffective amount of the compound administered by inhalation; and/or (e)the effective amount of the compound is administered by nasaladministration; or and/or (f) the effective amount of the compound isadministered by injection to the mammal; and/or (g) the effective amountof the compound is administered topically (dermal) to the mammal; and/or(h) the effective amount of the compound is administered by ophthalmicadministration; and/or (i) the effective amount of the compound isadministered rectally to the mammal.

In any of the aforementioned aspects are further embodiments in whichthe mammal is a human, including embodiments wherein the human has anasthmatic condition or one or more other condition(s) selected from thegroup consisting of allergic (extrinsic) asthma, non-allergic(intrinsic) asthma, acute severe asthma, chronic asthma, clinicalasthma, neutrophilic asthma, nocturnal asthma, allergen-induced asthma,aspirin-sensitive asthma, exercise-induced asthma, isocapnichyperventilation, child-onset asthma, adult-onset asthma, cough-variantasthma, occupational asthma, steroid-resistant asthma, or seasonalasthma, or chronic obstructive pulmonary disease, or pulmonaryhypertension or interstitial lung fibrosis. In any of the aforementionedaspects are further embodiments in which the mammal is an animal modelfor pulmonary inflammation, examples of which are provided herein.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce; (ii) the compound is administered to the mammal multiple timesover the span of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce daily; (ii) the compound is administered twice daily; (iii) thecompound is administered in cycles that include daily administration fora period of time followed by at least 1 day without administration; (iv)the compound is administered in cycles that include daily administrationfor a period of time followed by at least 1 day that includes a dosereduction in the daily amount of compound that is administered.

In any of the aforementioned aspects involving the treatment of PGD₂dependent diseases or conditions are further embodiments comprisingadministering at least one additional agent in addition to theadministartion of a compound having the structure of Formula (I). Invarious embodiments, each agent is administered in any order, includingsimultaneously. In certain embodiments, the at least one additionalagent is, by way of example only, an anti-inflammatory agent, adifferent compound having the structure of Formula (I), a DPIreceptorantagonist, a TP receptor antagonist, or a different DP₂ receptorantagonist.

In other embodiments, a compound of Formula (I) is combined with anadditional agent that is a respiratory agent, including, but not limitedto antihistamines (e.g., Zyrtec®), bronchodilators, LABAs (e.g.,salmeterol), theophylline, IgE modulators (e.g., Xolair® andomalizumab), steroids (e.g., fluticasone).

In further or alternative embodiments, the anti-inflammatory agent is,by way of example only, a leukotriene pathway modulator such as a CysLT1receptor antagonists (e.g., montelukast), a CysLT2 receptor antagonist,a 5-lipoxygenase inhibitor (e.g., zileuton), a 5-lipoxygenase-activatingprotein inhibitor (e.g., MK-0591, MK-886, DG-031 (BAY X1005),3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionicacid,3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionicacid), a LTA4 hydrolase inhibitor, a LTC₄ synthase inhibitor, a BLT1receptor antagonist or a BLT2 receptor antagonist.

In any of the aforementioned aspects involving the treatment ofproliferative disorders, including cancer, are further embodimentscomprising administering at least one additional agent, including by wayof example only alemtuzumab, arsenic trioxide, asparaginase (pegylatedor non-), bevacizumab, cetuximab, platinum-based compounds such ascisplatin, cladribine, daunorubicin/doxorubicin/idarubicin, irinotecan,fludarabine, 5-fluorouracil, gemtuzumab, methotrexate, Paclitaxel™,taxol, temozolomide, thioguanine, or classes of drugs including hormones(an antiestrogen, an antiandrogen, or gonadotropin releasing hormoneanalogues), interferons such as alpha interferon, nitrogen mustards suchas busulfan or melphalan or mechlorethamine, retinoids such astretinoin, topoisomerase inhibitors such as irinotecan or topotecan,tyrosine kinase inhibitors such as gefinitinib or imatinib, or agents totreat signs or symptoms induced by such therapy including allopurinol,filgrastim, granisetron/ondansetron/palonosetron, dronabinol.

In any of the aforementioned aspects involving the therapy of animmunogical disorder requiring immunosuppression or involving thetherapy of transplanted organs or tissues or cells are furtherembodiments comprising administering at least one additional agent,including by way of example only azathioprine, a corticosteroid,cyclophosphamide, cyclosporin, dacluzimab, mycophenolate mofetil, OKT3,rapamycin, tacrolimus, or thymoglobulin.

In any of the aforementioned aspects involving the therapy ofinterstitial cystitis are further embodiments comprising administeringat least one additional agent selected from, e.g., dimethylsulfoxide,omalizumab, and pentosan polysulfate.

In any of the aforementioned aspects involving the therapy of disordersof bone are further embodiments comprising administering at least oneadditional agent such as, by way of example only, minerals, vitamins,bisphosphonates, anabolic steroids, parathyroid hormone or analogs, andcathepsin K inhibitors dronabinol.

In any of the aforementioned aspects involving the prevention ortreatment of inflammation are further embodiments comprising: (a)monitoring inflammation in a mammal; (b) measuring bronchoconstrictionin a mammal; (c) measuring eosinophil and/or basophil and/or dendriticcell and/or neutrophil and/or monocyte and/or lymphocyte recruitment ina mammal; (d) monitoring mucosal secretion in a mammal; (e) measuringmucosal edema in a mammal.

In any of the aforementioned aspects the PGD₂-dependent or PGD₂ mediateddiseases or conditions include, but are not limited to, asthma,rhinitis, chronic obstructive pulmonary disease, pulmonary hypertension,interstitial lung fibrosis, arthritis, allergy, inflammatory boweldisease, adult respiratory distress syndrome, myocardial infarction,aneurysm, stroke, cancer, and endotoxic shock.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Prostaglandin D₂ (PGD₂) is an acidic lipid derived from the metabolismof arachidonic acid by cyclooxygenases and PGD₂ synthases. PGD₂ isproduced by mast cells, macrophages and Th2 lymphocytes in response tolocal tissue damage as well as in response allergic inflammationobserved in diseases such as asthma, rhinitis, and atopic dermatitis.More specifically, exogenous PGD₂ applied to bronchial airways elicitsmany responses that are characteristic of acute asthma.

PGD₂ is a major mast cell product that acts via two receptors, theD-type prostanoid (DP, also known as DPI) and the chemoattractantreceptor-homologous molecule expressed on Th2 cells (CRTH2, also knownas DP₂) receptors. DP₂ mediates the chemotaxis of eosinophils,basophils, and Th2 lymphocytes, and DP₁ receptor plays an important rolein eosinophil trafficking. DP₁ antagonists do not inhibit the release ofeosinophils when induced by the DP₂-selective agonists. However,eosinophils in human bone marrow specimens express DP₁ and DP₂ receptorsat similar levels and human peripheral blood expresses both DP₁ and DP₂,but the DP₁ receptor is expressed at lower levels. In agreement withthis, the chemotaxis of human peripheral blood eosinophils is inhibitedby both DP₁ and DP₂ antagonists. Accordingly, DP₁, DP₂ and dual DP₁/DP₂antagonists are useful in the treatment of allergic inflammation.

Activation of DP₂ is associated with chemotaxis and activation of Th2lymphocytes, eosinophils and basophils. In particular, PGD₂ binds to DP₂and mediates many of its effects through a G_(i)-dependent elevation ofintracellular calcium levels and reduction of cyclic AMP. In Th2lymphocytes, IL4, IL5 and IL13 cytokine production are also stimulatedby DP₂ activation. These cytokines have been implicated in numerousbiological actions including, by way of example only, immunoglobulin Eproduction, airway response, mucous secretion, and eosinophilrecruitment.

The terms CRTH2 and DP₂, refer to the same receptor and are usedinterchangeably herein. Likewise, another common name for DP is DP₁, andthe two terms are used interchangeably herein.

Illustrative Biological Activity

Prostaglandins (PGs) are recognized physiological lipid acid mediatorsproduced by the release of arachidonic acid from cell membranephospholipids and converted to prostaglandins by the action of COX₁ andCOX₂ cyclooxygenases and PG synthases. The cyclooxygenases sequentiallyconvert arachidonic acid to cyclic endoperoxide prostaglandin G₂ (PGG₂)and subsequently, prostaglandin H₂ (PGH₂). Depending on the tissue,physiological signal, and/or synthase type, PGH₂ can be converted tonumerous different prostaglandins, such as PGE₂, PGD₂, PGF₂α, and PGI₂as well as thromboxane A₂, another eicosanoid signaling molecule. Thesemediators then elicit a wide variety of physiological responsesincluding vasoconstriction or dilation, platelet aggregation, calciumtransport, pain sensitization, hormone release, inflammatory and immuneresponse, and cellular growth.

Prostaglandin D₂ is a major metabolite produced from the PGH₂intermediate via hematopoietic PGD₂ synthase or lipocalin PGD₂ synthase.In the brain and central nervous system, PGD₂ is produced and thought tofunction in pain perception and sleep regulation. In other tissues, PGD₂is produced primarily in immunoglobulin E (IgE) activated mast cells andto a lesser extent, in macrophages, dendritic cells, T helper 2 (Th2)lymphocytes and other leukocytes. In the cell, PGD₂ is rapidlymetabolized and converted to other downstream effectors includingΔ²PGJ₂, 9α11βPGF₂, 13,14-dihydro-15-keto-PGD₂, and15-deoxy-Δ^(12,14)PGD₂.

Mast-cell-derived PGD₂ is produced in high concentrations in response toan allergen challenge. Studies in preclinical species have observed thefollowing features when PGD₂ is applied to in vivo preparations, or itsoverproduction is engineered by genetic manipulation:

-   -   Vasodilatation leading to erythema (flare) and -potentiation of        oedema (wheal).    -   Recruitment of eosinophils and Th2 lymphocytes.    -   Modulation of Th2-cytokine production.    -   Bronchoconstriction.

Injection of PGD₂ into human skin has been shown to produce a longlasting erythema, to potentiate the effects of other mediators oninduration and leukocyte infiltration in human skin and to enhanceoedema formation in rat skin. It is most likely that these effects ofPGD₂, like those of other vasodilator prostaglandins, are due to anincreased blood flow to the inflamed lesion and are, therefore, mostlikely to be mediated predominantly by the DP₁ receptor. Although theseobservations make it clear that DP₁ mediates the vascular effects ofPGD₂, the capacity of PGD₂ to promote the cellular changes associatedwith inflammation is not due to an action on DP₁.

The main receptors that are activated by PGD₂ or its metabolites andmediate its effects are DP₁, CRTH2 (or DP₂) and TP.

DP₁ (or DP) is a G-protein coupled seven-transmembrane receptor that,upon activation by PGD₂ binding, leads to an increase in intracellularcAMP levels. DP₁ is expressed in the brain, bronchial smooth muscle,vascular and airway smooth muscle, dendritic cells, and platelets andinduces PGD₂ dependent bronchodilation, vasodilation, plateletaggregation inhibition, and suppression of cytokine production. Geneticanalysis of DP₁ function using knock-out mice has shown that micelacking DP do not develop asthmatic responses in an ovalbumin-inducedasthma model. Analysis of selective DP anatgonists in guinea pigallergic rhinitis models demonstrated dramatic inhibition of early nasalresponses, as assessed by sneezing, mucosal plasma exudation andeosinophil infiltration. DP antagonism alleviates allergen-inducedplasma exudation in the conjunctiva in a guinea pig allergicconjuctivitis model and antigen-induced esinophil infiltration into thelung in a guinea pig asthma model.

Much of the pro-inflammatory activity of PGD₂ is through interactionwith DP₂ (or CRTH2). DP₂ is a G-protein coupled receptor and istypically highly expressed in Th2 lymphocytes, eosinophils andbasophils. DP₂ activation functions to directly activate and recruit Th2lymphocytes and eosinophils. Activated Th2 lymphocytes produce andsecrete inflammatory cytokines including IL4, IL5, and IL13. Despitebinding PGD₂ with a similar affinity as DP₁, DP₂ is not structurallyrelated to DP₁ and signals through a different mechanism—the effects ofDP₂ are mediated through Gi-dependent elevation in intracellular calciumlevels and reduction in intracellular levels of cyclic AMP. DP₂activation is important in eosinophil recruitment in response toallergic challenge in such tissues as nasal mucosa, bronchial airways,and skin. The application of either PGD₂ or selective DP₂ agonists bothexacerbate and enhance allergic responses in lung and skin. DP₂activation appears to have a crucial role in mediating allergicresponses, and thus the use of antagonists of PGD₂ activation of the DP₂receptor are an attractive approach to treat the inflammatory componentof allergic diseases such as asthma, rhinitis, and dermatitis.

TP receptors primarily function to antagonize DP₁ receptor's effectssuch as promoting bronchoconstriction, vasoconstriction, and plateletaggregation. While TP receptor's main ligand is thromboxane A₂, it alsobinds and is activated by the PGD₂ derivative, 9α11βPGF₂. TP is aGq-coupled prostanoid receptor that binds thromboxane with highaffinity, promoting platelet aggregation and constriction of bothvascular and airway smooth muscle. PGD₂ activates the TP receptor inhuman bronchial muscle, probably through the formation of the11-ketoreductase metabolite 9α11βPGF2. The bronchoconstrictor effects ofTP dominate over the bronchodilator effects of DP₁ in the airways.

DP₁ and DP₂ have crucial, and complementary, roles in the physiologicalresponse of animals to PGD₂ and blockade of either one or both of thesereceptors may prove beneficial in alleviating allergic diseases orconditions triggered by PGD₂, such as, but not limited to, allergicrhinitis, asthma, dermatitis, and allergic conjunctivitis.

Compounds

Compounds of any of Formula (I), including pharmaceutically acceptablesalts, pharmaceutically acceptable prodrugs, and pharmaceuticallyacceptable solvates thereof, antagonize or modulate DP₂ and are used totreat patients suffering from PGD₂-dependent or PGD₂ mediated conditionsor diseases, including, but not limited to, asthma, rhinitis,dermatitis, and inflammatory conditions.

In one aspect is a compound having the structure of Formula (I),pharmaceutically acceptable salt, pharmaceutically acceptable solvate,N-oxide, or prodrug thereof:

-   -   wherein,    -   ring A is a substituted or unsubstituted heteroarylene, wherein        if ring A is substituted, then each substituent on ring A is        independently selected from H and R^(A);    -   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —NR¹³—, —C(R¹⁶)₂—, or —C(═O)—;    -   Q is —C(═O)-Q¹, tetrazolyl, or a carboxylic acid bioisostere;        -   Q¹ is —OR¹⁵, —NHSO₂R⁹, —N(R¹⁰)₂, —NH—OH, or —NH—CN;    -   each R¹ is independently selected from H, halogen, C₁-C₄alkyl,        and C₁-C₄haloalkyl;    -   each of R², R³, R⁴ and R⁵ is independently selected from H,        halogen, —CN, —NO₂, —OH, —OR¹⁰, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹,        —N(R¹⁰)S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰,        —OCO₂R¹⁰, —N(R¹⁰)₂, —NHCH₂CO₂R¹⁰, —OCH₂CO₂R¹⁰, —SCH₂CO₂R¹⁰,        —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂, —NR¹⁰C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R⁹,        —NR¹⁰—C₁-C₄alkyl-C(═O)R⁹, —NR¹⁰C(═O)OR⁹, C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy,        C₁-C₆heteroalkyl, a substituted or unsubstituted cycloalkyl, a        substituted or unsubstituted heterocycloalkyl, a substituted or        unsubstituted aryl, a substituted or unsubstituted heteroaryl, a        substituted or unsubstituted —C₁-C₆alkylene-cycloalkyl, a        substituted or unsubstituted —C₁-C₆alkylene-heterocycloalkyl, a        substituted or unsubstituted —C₁-C₆alkylene-aryl, and a        substituted or unsubstituted —C₁-C₆alkylene-heteroaryl;    -   each R^(A) is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR¹⁰, —SR⁹, S(═O)R⁹, —S(═O)₂R⁹, —N(R¹⁰)S(═O)₂R⁹,        —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —OCO₂R¹⁰,        —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂, —NR¹⁰C(═O)N(R¹⁰)₂,        —NR¹⁰C(═O)R⁹, —NR¹⁰C(═O)OR⁹, C₁-C₆alkyl, C₁-C₆fluoroalkyl,        C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, a substituted        or unsubstituted cycloalkyl, and a substituted or unsubstituted        heterocycloalkyl;    -   each R⁶ is each independently selected from H, halogen,        C₁-C₄alkyl, and C₁-C₄haloalkyl;    -   Z is —N—R⁷—, —S—, —S(═O)—, —S(═O)₂— or —O—;    -   R⁷ is —C(═O)R¹¹, —C(═O)OR¹², —C(═O)N(R¹³)₂, —S(═O)₂N(R¹³)2 or        —S(═O)₂R¹²;        -   R¹¹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a            substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted            or unsubstituted heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted            heteroaryl, a substituted or unsubstituted            —C₁-C₆alkylene-cycloalkyl, a substituted or unsubstituted            —C₁-C₆alkylene-heterocycloalkyl, a substituted or            unsubstituted —C₁-C₆alkylene-aryl or a substituted or            unsubstituted —C₁-C₆alkylene-heteroaryl; or        -   R¹¹ is -L³-X³-Q³;            -   L³ is a —C₁-C₆alkylene-;            -   X³ is a bond, —O—, —S—, —S(═O)—, —S(═O)₂—, or —NR¹³—;            -   Q³ is a C₁-C₆alkyl, C₁-C₆fluoroalkyl a substituted or                unsubstituted C₃-C₁₀cycloalkyl, a substituted or                unsubstituted heterocycloalkyl, a substituted or                unsubstituted aryl, a substituted or unsubstituted                heteroaryl, a substituted or unsubstituted                C₁-C₆alkylene-C₃-C₁₀cycloalkyl, a substituted or                unsubstituted C₁-C₆alkylene-heterocycloalkyl, a                substituted or unsubstituted C₁-C₆alkylene-aryl, or a                substituted or unsubstituted C₁-C₆alkylene-heteroaryl;        -   R¹² is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a            substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted            or unsubstituted heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted            heteroaryl, a substituted or unsubstituted            —C₁-C₆alkylene-cycloalkyl, a substituted or unsubstituted            —C₁-C₆alkylene-heterocycloalkyl, a substituted or            unsubstituted —C₁-C₆alkylene-aryl or a substituted or            unsubstituted —C₁-C₆alkylene-heteroaryl;        -   each R¹³ is independently H, —CN, C₁-C₆alkyl,            C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a substituted or            unsubstituted C₃-C₁₀cycloalkyl, a substituted or            unsubstituted heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted            heteroaryl, a substituted or unsubstituted            —C₁-C₆alkylene-cycloalkyl, a substituted or unsubstituted            —C₁-C₆alkylene-heterocycloalkyl, a substituted or            unsubstituted —C₁-C₆alkylene-aryl or a substituted or            unsubstituted —C₁-C₆alkylene-heteroaryl; or        -   two R¹³ groups attached to the same N atom are taken            together with the N atom to which they are attached to form            a substituted or unsubstituted heterocycle;    -   R⁸ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl, a        substituted or unsubstituted cycloalkyl, a substituted or        unsubstituted heterocycloalkyl, a substituted or unsubstituted        aryl, or a substituted or unsubstituted heteroaryl,        C₁-C₆alkylene-R¹⁴, —C₁-C₆alkylene-O—R¹⁴, —C₁-C₆alkylene-S—R¹⁴,        —C₁-C₆alkylene-S(═O)—R¹⁴, —C₁-C₆alkylene-S(═O)₂—R¹⁴,        —C₁-C₆alkylene-N(R¹⁴)₂, —C₁-C₆alkylene-C(═O)—R¹⁴,        —C₁-C₆alkylene-C(═O)O—R¹⁴—, —C₁-C₆alkylene-OC(═O)—R¹⁴,        —C₁-C₆alkylene-NR¹⁴C(═O)—R¹⁴ or —C₁-C₆alkylene-C(═O)N(R¹⁴)₂;        -   each R¹⁴ is independently selected from H, C₁-C₆alkyl,            C₁-C₆heteroalkyl, C₁-C₆haloalkyl, a substituted or            unsubstituted cycloalkyl, a substituted or unsubstituted            heterocycloalkyl, a substituted or unsubstituted aryl, a            substituted or unsubstituted benzyl, a substituted or            unsubstituted naphthyl, or a substituted or unsubstituted            heteroaryl; or        -   two R¹⁴ groups attached to the same nitrogen are taken            together with the nitrogen atom to which they are attached            to form a substituted or unsubstituted heterocycle; or    -   R⁷ and R⁸ are taken together with the N atom to which they are        attached to form a substituted or unsubstituted heterocycle;    -   R⁹ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a        substituted or unsubstituted cycloalkyl, a substituted or        unsubstituted heterocycloalkyl, a substituted or unsubstituted        aryl, a substituted or unsubstituted heteroaryl, a substituted        or unsubstituted —C₁-C₄alkylene-cycloalkyl, a substituted or        unsubstituted —C₁-C₄alkylene-heterocycloalkyl, a substituted or        unsubstituted —C₁-C₄alkylene-aryl, or a substituted or        unsubstituted —C₁-C₄alkylene-heteroaryl;    -   each R¹⁰ is independently selected from H, C₁-C₆alkyl,        C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a substituted or        unsubstituted cycloalkyl, a substituted or unsubstituted        heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl, a substituted or        unsubstituted —C₁-C₄alkylene-cycloalkyl, a substituted or        unsubstituted —C₁-C₄alkylene-heterocycloalkyl, a substituted or        unsubstituted —C₁-C₄alkylene-aryl, and a substituted or        unsubstituted —C₁-C₄alkylene-heteroaryl; or    -   two R¹⁰ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted heterocycle;    -   R¹⁵ is selected from H and C₁-C₆alkyl; and    -   each R¹⁶ is independently selected from H, —OH, halogen, —CN,        C₁-C₆alkyl.

For any and all of the embodiments, substituents can be selected fromamong from a subset of the listed alternatives. For example. In someembodiments, Q is —C(═O)-Q¹ or tetrazolyl. In some embodiments, Q¹ is—OR⁵. In some embodiments, R¹⁵ is H, —CH₃, or —CH₂CH₃. In otherembodiments, R¹⁵ is H.

In some embodiments, Q is —CO₂H, —CO₂CH₃, or —CO₂CH₂ CH₃. In otherembodiments, Q is —CO₂H.

In one aspect, each R¹ is independently selected from H, F, andC₁-C₄alkyl. In another aspect, each R¹ is independently selected from H,F, and —CH₃. In yet another aspect, each R¹ is independently selectedfrom H and —CH₃. In one aspect, each R¹ is H.

In one aspect, each R⁶ is independently selected from H, and C₁-C₄alkyl.In another aspect, each R⁶ is independently selected from H and —CH₃. Inone aspect, each R⁶ is H.

In one aspect, the groups

are on non-adjacent atoms of ring A.

In some embodiments, the groups

are in a meta orientation with respect to each other on ring A. In someembodiments, X and

are in a para orientation with respect to each other on ring A. In someembodiments, X and

are in a ortho orientation with respect to each other on ring A.

In some embodiments, X is —O—, —S—, or —C(R¹⁶)₂—. In some otherembodiments, X is —O— or —C(R¹⁶)₂—. In other embodiments, X is—C(CH₃)H—, —C(CH₃)₂—, or —CH₂—. In one aspect, X is —CH₂—. In some otherembodiments, X is —O—.

In some embodiments, each of R², R³, and R⁵ is independently selectedfrom H, halogen, —CN, —NO₂, —OH, —OR¹⁰, —S(═O)₂R⁹, —N(R¹)S(═O)₂R⁹,—S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —OCO₂R¹⁰, —N(R¹⁰)₂,—C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂, —NR¹⁰C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R⁹,—NR¹⁰C(═O)OR⁹, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,C₁-C₆alkoxy, and C₁-C₆heteroalkyl.

In some embodiments, each of R², R³, and R⁵ is independently selectedfrom H, halogen, —CN, —NO₂, —OH, —OR¹⁰, —N(R¹⁰)₂, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl.

In other embodiments, at least one of R², R³, and R⁵ are H. In someother embodiments, at least two of R², R³, and R⁵ are H. In someembodiments, each of R², R³, and R⁵ is H.

In one aspect, the compound of Formula (I) has the following structure:

In one aspect, the compound of Formula (I) has the following structure:

In some embodiments, R¹⁵ is H, —CH₃, or —CH₂CH₃. In other embodiments,R¹⁵ is H.

In some embodiments, ring A is a substituted or unsubstituted monocyclicheteroarylene, where ring A contains 0-1 oxygen atoms; 0-1 sulfur atoms;and 0-4 nitrogen atoms, wherein if ring A is substituted, then eachsubstituent on ring A is independently selected from H and R^(A).

In other embodiments, ring A is a substituted or unsubstitutedheteroarylene selected from pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl,isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isothiazolyl, triazolyl,tetrazolyl, wherein if ring A is substituted, then each substituent onring A is independently selected from H and R^(A).

In some other embodiments, ring A is a substituted or unsubstitutedmonocyclic heteroarylene ring, where ring A contains 0-1 oxygen atoms;0-1 sulfur atoms; and 1-4 nitrogen atoms, wherein if ring A issubstituted, then each substituent on ring A is independently selectedfrom H and R^(A).

In yet other embodiments, ring A is a substituted or unsubstituted5-membered monocyclic heteroarylene, where ring A contains 0-1 oxygenatoms; 0-1 sulfur atoms; and 1-4 nitrogen atoms, wherein if ring A issubstituted, then each substituent on ring A is independently selectedfrom H and R^(A).

In some embodiments, ring A is a substituted or unsubstitutedheteroarylene selected from pyrrolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, imidazolyl, pyrazolyl, isothiazolyl, triazolyl, andtetrazolyl, wherein if ring A is substituted, then each substituent onring A is independently selected from H and R^(A). In some embodiments,ring A is a pyrazolyl ring. In some embodiments, ring A is a triazolylring. In other embodiments, ring A is a oxadiazolyl ring.

In some embodiments, ring A is a substituted or unsubstituted 6-memberedmonocyclic heteroarylene ring, where ring A contains 1-3 nitrogen atoms,wherein if ring A is substituted, then each substituent on ring A isindependently selected from H and R^(A).

In some other embodiments, ring A is a substituted or unsubstitutedheteroarylene selected from pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl and triazinyl, wherein if ring A is substituted, then eachsubstituent on ring A is independently selected from H and R^(A). Insome embodiments, ring A is a pyridinyl ring. In other embodiments, ringA is a pyrimidinyl ring.

In some embodiments, R⁴ is selected from halogen, —CN, —NO₂, —OH, —OR¹⁰,—SR⁹, —S(═O)R⁹, —S(═O)₂R⁹, —N(R¹⁰)S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹,—OC(═O)R⁹, —CO₂R^(o), —OCO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂,—NR¹⁰C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R⁹, —NR¹⁰—C₁-C₄alkyl-C(═O)R⁹,—NR¹⁰C(═O)OR⁹, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,C₁-C₆alkoxy, C₁-C₆heteroalkyl, a substituted or unsubstitutedcycloalkyl, a substituted or unsubstituted heterocycloalkyl, asubstituted or unsubstituted aryl, and a substituted or unsubstitutedheteroaryl.

In some embodiments, each R^(A) is independently selected from H,halogen, —CN, —NO₂, —OH, —OR¹⁰, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹,—N(R¹⁰)S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —N(R¹⁰)₂, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, asubstituted or unsubstituted cycloalkyl, and a substituted orunsubstituted heterocycloalkyl.

In yet embodiments, each R^(A) is each independently H, halogen, —CN,—OH, —OR¹⁰, —N(R¹⁰)₂, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,C₁-C₆alkoxy, or C₁-C₆heteroalkyl.

In some embodiments, each R^(A) is each independently H, halogen, CN,—OH, —OCH₃, —CH₃, —CF₃, or —OCF₃.

In one aspect, at least one R^(A) is H. In some embodiments, ring A isunsubstituted. In some embodiments, if ring A is substituted, then ringA is substituted with 1 or 2 R^(A). In some embodiments, if ring A issubstituted, then ring A is substituted with 1 R^(A).

In some embodiments, R⁴ is selected from halogen, —CN, —NO₂, —OH, —OR¹⁰,—S(═O)₂R⁹, —NHS(═O)₂R⁹, —N(C₁-C₆alkyl)S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,—C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —OCO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,—OC(═O)N(R¹⁰)₂, —NHC(═O)N(R¹⁰)₂, —N(C₁-C₆alkyl)C(═O)N(R¹⁰)₂, —NHC(═O)R⁹,—N(C₁-C₆alkyl)C(═O)R⁹, —NH—C₁-C₄alkylene-C(═O)R⁹, —NHC(═O)OR⁹,—N(C₁-C₆alkyl)C(═O)OR⁹, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,C₁-C₆alkoxy, C₁-C₆heteroalkyl, a substituted or unsubstitutedcycloalkyl, a substituted or unsubstituted heterocycloalkyl, asubstituted or unsubstituted aryl, and a substituted or unsubstitutedheteroaryl.

In some other embodiments, R⁴ is selected from halogen, —CN, —NO₂, —OH,—OR¹⁰, —S(═O)₂R⁹, —NHS(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹,—CO₂R¹⁰, —OCO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂,—NHC(═O)N(R¹⁰)₂, —NHC(═O)R⁹, —NH—C₁-C₄alkylene-C(═O)R⁹, —NHC(═O)OR⁹,C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy,C₁-C₆heteroalkyl, a substituted or unsubstituted cycloalkyl, asubstituted or unsubstituted heterocycloalkyl, a substituted orunsubstituted aryl, and a substituted or unsubstituted heteroaryl.

In yet other embodiments, R⁴ is selected from —NO₂, —NHS(═O)₂R⁹,—N(R¹⁰)₂, —NHC(═O)N(R¹⁰)₂, —NHC(═O)R⁹, —NH—C₁-C₄alkylene-C(═O)R⁹, and—NHC(═O)OR⁹.

In some embodiments, R⁴ is selected from a substituted or unsubstitutedcycloalkyl, a substituted or unsubstituted heterocycloalkyl, asubstituted or unsubstituted aryl, and a substituted or unsubstitutedheteroaryl.

In some embodiments, R⁴ is selected from halogen, —CN, —NO₂, —OH, —OR1,—S(═O)₂R⁹, —NHS(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰,—N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂, —NHC(═O)N(R¹⁰)₂, —NHC(═O)R⁹,C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, and C₁-C₆alkoxy.

In some embodiments, R⁴ is selected from halogen, —NHS(═O)₂R⁹,—S(═O)₂NHR¹⁰, —NHC(═O)R⁹, —C(═O)NHR¹⁰, —NHC(═O)NHR¹⁰, —NHC(═O)OR⁹,C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, and C₁-C₆alkoxy.

In some embodiments, R⁹ is C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆fluoroalkyl, a substituted or unsubstituted cycloalkyl, asubstituted or unsubstituted aryl, a substituted or unsubstitutedheteroaryl, a substituted or unsubstituted —C₁-C₄alkylene-cycloalkyl, asubstituted or unsubstituted —C₁-C₄alkylene-aryl, or a substituted orunsubstituted —C₁-C₄alkylene-heteroaryl.

In some embodiments, R⁹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, a substitutedor unsubstituted cycloalkyl, a substituted or unsubstituted phenyl, asubstituted or unsubstituted naphthyl, a substituted or unsubstitutedmonocyclic heteroaryl, a substituted or unsubstituted bicyclicheteroaryl, a substituted or unsubstituted —CH₂-cycloalkyl, asubstituted or unsubstituted —CH₂-phenyl, a substituted or unsubstituted—CH₂-naphthyl, a substituted or unsubstituted —CH₂— (monocyclicheteroaryl), or a substituted or unsubstituted —CH₂— (bicyclicheteroaryl). In some embodiments, R⁹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₃-C₆ cycloalkyl, a substituted or unsubstituted phenyl, a substitutedor unsubstituted monocyclic C₁-C₅heteroaryl, —CH₂—C₃-C₆cycloalkyl, asubstituted or unsubstituted —CH₂-phenyl, a substituted or unsubstituted—CH₂-(monocyclic C₁-C₅heteroaryl). In some embodiments, R⁹ isC₁-C₆alkyl, C₁-C₆fluoroalkyl, C₃-C₆cycloalkyl, a substituted orunsubstituted phenyl, or a substituted or unsubstituted —CH₂-phenyl. Insome embodiments, R⁹ is C₁-C₆alkyl, C₃-C₆cycloalkyl, or a substituted orunsubstituted phenyl.

In some embodiments, each R¹⁰ is independently selected from H,C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a substituted orunsubstituted cycloalkyl, a substituted or unsubstituted aryl, asubstituted or unsubstituted heteroaryl, a substituted or unsubstituted—C₁-C₄alkylene-cycloalkyl, a substituted or unsubstituted—C₁-C₄alkylene-aryl, and a substituted or unsubstituted—C₁-C₄alkylene-heteroaryl.

In some embodiments, each R¹⁰ is independently selected from H,C₁-C₆alkyl, C₁-C₆fluoroalkyl, a substituted or unsubstituted cycloalkyl,a substituted or unsubstituted phenyl, a substituted or unsubstitutednaphthyl, a substituted or unsubstituted monocyclic heteroaryl, asubstituted or unsubstituted bicyclic heteroaryl, a substituted orunsubstituted —CH₂-cycloalkyl, a substituted or unsubstituted—CH₂-phenyl, a substituted or unsubstituted —CH₂-napthyl, a substitutedor unsubstituted —CH₂— (monocyclic heteroaryl), and a substituted orunsubstituted —CH₂— (bicyclic heteroaryl).

In some embodiments, each R¹⁰ is independently selected from H,C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₃-C₆cycloalkyl, a substituted orunsubstituted phenyl, a substituted or unsubstituted monocyclicheteroaryl, a substituted or unsubstituted —CH₂—C₃-C₆cycloalkyl, asubstituted or unsubstituted —CH₂-phenyl, and a substituted orunsubstituted —CH₂-(monocyclic heteroaryl). In some embodiments, eachR¹⁰ is independently selected from H, C₁-C₆alkyl, C₃-C₆cycloalkyl, asubstituted or unsubstituted phenyl, and a substituted or unsubstituted—CH₂-phenyl.

In some embodiments, Z is —S—, —S(═O)—, —S(═O)₂— or —O—. In someembodiments, Z is —O—. In other embodiments, Z is —S—, —S(═O)—, or—S(═O)₂—.

In some embodiments, Z is —N—R⁷; and R⁷ is —C(═O)R¹¹, —C(═O)OR¹²,—C(═O)N(R¹³)₂, —S(═O)₂N(R¹³)₂ or —S(═O)₂R¹².

In some embodiments, Z is —N—R⁷; and R⁷ is —C(═O)R¹¹, —C(═O)OR¹², or—C(═O)N(R¹³)₂.

In one aspect, Z is —N—R⁷; and R⁷ is —C(═O)R.

In some embodiments, R¹¹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, a substituted or unsubstituted C₃-C₁₀cycloalkyl, asubstituted or unsubstituted heterocycloalkyl, a substituted orunsubstituted aryl, a substituted or unsubstituted heteroaryl, asubstituted or unsubstituted —C₁-C₆alkylene-cycloalkyl, a substituted orunsubstituted —C₁-C₆alkylene-heterocycloalkyl, a substituted orunsubstituted —C₁-C₆alkylene-aryl or a substituted or unsubstituted—C₁-C₆alkylene-heteroaryl.

In some other embodiments, R¹¹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, a substituted or unsubstituted C₃-C₁₀cycloalkyl, asubstituted or unsubstituted aryl, a substituted or unsubstitutedheteroaryl, a substituted or unsubstituted —C₁-C₆alkylene-cycloalkyl, asubstituted or unsubstituted —C₁-C₆alkylene-aryl or a substituted orunsubstituted —C₁-C₆alkylene-heteroaryl.

In yet other embodiments, R¹¹ is a substituted or unsubstituted aryl, asubstituted or unsubstituted heteroaryl, a substituted or unsubstituted—C₁-C₆alkylene-aryl or a substituted or unsubstituted—C₁-C₆alkylene-heteroaryl.

In some other embodiments, R¹¹ is a substituted or unsubstituted phenyl,a substituted or unsubstituted naphthyl, a substituted or unsubstitutedmonocyclic heteroaryl, a substituted or unsubstituted bicyclicheteroaryl, a substituted or unsubstituted —CH₂-phenyl, a substituted orunsubstituted —CH₂-naphthyl, a substituted or unsubstituted—CH₂-(monocyclic heteroaryl), or a substituted or unsubstituted —CH₂—(bicyclic heteroaryl).

In some embodiments, R¹¹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, or a substituted or unsubstituted C₃-C₁₀cycloalkyl.

In one aspect, Z is —N—R⁷; and R⁷ is —C(═O)OR¹².

In some embodiments, R¹² is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, a substituted or unsubstituted C₃-C₁₀cycloalkyl, asubstituted or unsubstituted heterocycloalkyl, a substituted orunsubstituted aryl, a substituted or unsubstituted heteroaryl, asubstituted or unsubstituted —C₁-C₆alkylene-cycloalkyl, a substituted orunsubstituted —C₁-C₆alkylene-heterocycloalkyl, a substituted orunsubstituted —C₁-C₆alkylene-aryl or a substituted or unsubstituted—C₁-C₆alkylene-heteroaryl.

In other embodiments, R¹² is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, a substituted or unsubstituted C₃-C₁₀cycloalkyl, asubstituted or unsubstituted aryl, a substituted or unsubstitutedheteroaryl, a substituted or unsubstituted —C₁-C₆alkylene-cycloalkyl, asubstituted or unsubstituted —C₁-C₆alkylene-aryl or a substituted orunsubstituted —C₁-C₆alkylene-heteroaryl.

In some other embodiments, R¹² is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, a substituted or unsubstituted C₃-C₁₀cycloalkyl, asubstituted or unsubstituted —C₁-C₆alkylene-cycloalkyl, a substituted orunsubstituted —C₁-C₆alkylene-aryl or a substituted or unsubstituted—C₁-C₆alkylene-heteroaryl.

In some embodiments, R¹² is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, a substituted or unsubstituted —CH₂-cycloalkyl, asubstituted or unsubstituted —CH₂-phenyl, a substituted or unsubstituted—CH₂-napthyl, a substituted or unsubstituted —CH₂— (monocyclicheteroaryl), or a substituted or unsubstituted —CH₂— (bicyclicheteroaryl).

In some embodiments, R¹² is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, or a substituted or unsubstituted C₃-C₁₀cycloalkyl.

In one aspect, Z is —N—R⁷; and R⁷ is —C(═O)N(R¹³)₂

In some embodiments, each R¹³ is independently H, —CN, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a substituted or unsubstitutedC₃-C₁₀cycloalkyl, a substituted or unsubstituted heterocycloalkyl, asubstituted or unsubstituted aryl, a substituted or unsubstitutedheteroaryl, a substituted or unsubstituted —C₁-C₆alkylene-cycloalkyl, asubstituted or unsubstituted —C₁-C₆alkylene-heterocycloalkyl, asubstituted or unsubstituted —C₁-C₆alkylene-aryl or a substituted orunsubstituted —C₁-C₆alkylene-heteroaryl; or two R¹³ groups attached tothe same N atom are taken together with the N atom to which they areattached to form a substituted or unsubstituted heterocycle.

In some other embodiments, each R¹³ is independently H, —CN, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a substituted or unsubstitutedC₃-C₁₀cycloalkyl, a substituted or unsubstituted aryl, a substituted orunsubstituted heteroaryl, a substituted or unsubstituted—C₁-C₆alkylene-aryl or a substituted or unsubstituted—C₁-C₆alkylene-heteroaryl

In other embodiments, each R¹³ is independently H, —CN, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a substituted or unsubstitutedC₃-C₁₀cycloalkyl, a substituted or unsubstituted aryl, a substituted orunsubstituted heteroaryl, a substituted or unsubstituted—C₁-C₆alkylene-aryl or a substituted or unsubstituted—C₁-C₆alkylene-heteroaryl.

In yet other embodiments, each R¹³ is independently H, —CN, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a substituted or unsubstituted—C₁-C₆alkylene-aryl or a substituted or unsubstituted—C₁-C₆alkylene-heteroaryl.

In some embodiments, each R¹³ is independently H, —CN, C₁-C₆alkyl,C₁-C₆fluoroalkyl, a substituted or unsubstituted —CH₂-phenyl, asubstituted or unsubstituted —CH₂-napthyl, a substituted orunsubstituted —CH₂— (monocyclic heteroaryl), or a substituted orunsubstituted —CH₂— (bicyclic heteroaryl).

In some embodiments, each R¹³ is independently H, C₁-C₆alkyl, orC₁-C₆fluoroalkyl.

In one aspect, Z is —N—R⁷; and R⁷ is —S(═O)₂N(R¹³)₂ or —S(═O)₂R¹². Insome embodiments, Z is —N—R⁷; and R⁷ is —S(═O)₂R¹²;

In some embodiments, R¹² is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, a substituted or unsubstituted aryl, a substituted orunsubstituted heteroaryl.

In some embodiments, R⁸ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,a substituted or unsubstituted cycloalkyl, a substituted orunsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, ora substituted or unsubstituted heteroaryl, C₁-C₆alkylene-R¹⁴,—C₁-C₆alkylene-O—R¹⁴, —C₁-C₆alkylene-N(R¹⁴)₂, —C₁-C₆alkylene-C(═O)—R¹⁴,—C₁-C₆alkylene-C(═O)O—R¹⁴—, or —C₁-C₆alkylene-C(═O)N(R¹⁴)₂; each R¹⁴ isindependently selected from H, C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, a substituted or unsubstituted cycloalkyl, a substitutedor unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl,a substituted or unsubstituted benzyl, a substituted or unsubstitutednaphthyl, or a substituted or unsubstituted heteroaryl; or two R¹⁴groups attached to the same nitrogen are taken together with thenitrogen atom to which they are attached to form a substituted orunsubstituted C₃-C₆heterocycloalkyl

In some other embodiments, R⁸ is C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, a substituted or unsubstituted cycloalkyl, a substitutedor unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl,or a substituted or unsubstituted heteroaryl, C₁-C₆alkylene-R¹⁴,—C₁-C₆alkylene-O—R¹⁴, —C₁-C₆alkylene-N(R¹⁴)₂,—C₁-C₆alkylene-C(═O)O—R¹⁴—, or —C₁-C₆alkylene-C(═O)N(R¹⁴)₂; each R¹⁴ isindependently selected from H, and C₁-C₆alkyl.

In other embodiments, R⁸ is C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, a substituted or unsubstituted cycloalkyl, a substitutedor unsubstituted aryl, a substituted or unsubstituted heteroaryl,C₁-C₆alkylene-R¹⁴, or —C₁-C₆alkylene-O—R¹⁴; R¹⁴ is selected from H,C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl, a substituted orunsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, a substituted orunsubstituted benzyl, and a substituted or unsubstituted heteroaryl.

In some other embodiments, R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆heteroalkyl, (a substituted or unsubstituted monocyclic or bicycliccycloalkyl) or C₁-C₆alkylene-R¹⁴; R¹⁴ is a substituted or unsubstitutedaryl, or a substituted or unsubstituted heteroaryl.

In some embodiments, R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl, orC₁-C₆heteroalkyl.

In some embodiments, R⁸ is C₁-C₆alkylene-R¹⁴; R¹⁴ is a substituted orunsubstituted aryl, or a substituted or unsubstituted heteroaryl.

In some embodiments, R⁸ is isopropyl, tert-butyl, —CH₂CF₃, —CH₂CO₂H,—CH₂CH₂N(CH₃)₂, phenyl, 4-chlorophenyl, benzyl, phenethyl, thiazol-2-yl,5-methyl-[1,3,4]thiadiazol-2-yl, pyridin-2-yl, or quinolin-2-yl. In someembodiments, R⁸ is as defined in Table 1 and/or Table 2.

In some embodiments, R⁹ is as defined in Table 1 and/or Table 2.

In one aspect, Z is —N—R⁷; and R⁷ and R⁸ are taken together with thenitrogen atom to which they are attached to form a substituted orunsubstituted heterocycle.

In some embodiments, ring A is selected from:

or N-oxides thereof.

In some embodiments, ring A is as described in Table 1 and/or Table 2.

Any combination of the groups described above for the various variablesis contemplated herein.

In one aspect, compounds of Formula (I) include, but are not limited to,those described in Tables 1 and 2:

TABLE 1

Cmpd # Ring A Q X R⁸ R⁹ 1-1

2H-Tetrazol-5-y1 —CH₂— tert-butyl tert-butyl 1-2

—CO₂H —CH₂— tert-butyl tert-butyl 1-3

—CO₂H —CH₂— tert-butyl tert-butyl

TABLE 2 Cmpd # Ring A Q X R⁸ R⁹ 2-1

—CO₂H —CH₂— tert-butyl tert-butyl 2-2

—CO₂H —CH₂— tert-butyl cyclopropyl 2-3

—CO₂H —CH₂— tert-butyl tert-butyl 2-4

—CO₂H —CH₂— isopropyl 4-trifluoromethyl- phenyl 2-5

—CO₂H —CH₂— tert-butyl 2,4- dichlorophenyl 2-6

—CO₂H —CH₂— 2,2,2- trifluoroethyl tert-butyl 2-7

—CO₂H —O— tert-butyl tert-butyl 2-8

—CO₂H —O— tert-butyl tert-butyl 2-9

—CO₂H —O— tert-butyl tert-butyl

Synthesis of Compounds

Compounds of Formula (I) described in the prior section are synthesizedusing standard synthetic techniques or using methods known in the art incombination with methods described herein. In additions, solvents,temperatures and other reaction conditions presented herein may vary.

The starting material used for the synthesis of the compounds of Formula(I) described in the prior section are eith synthesized or obtained fromcommercial sources, such as, but not limited to, Aldrich Chemical Co.(Milwaukee, Wis.), or Sigma Chemical Co. (St. Louis, Mo.). The compoundsdescribed herein, and other related compounds having differentsubstituents are synthesized using known techniques and materials,including those found in March, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed.,(Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed.,Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPSIN ORGANIC SYNTHESIS 3^(rd) Ed., (Wiley 1999). General methods for thepreparation of compounds can be modified by the use of appropriatereagents and conditions for the introduction of the various moietiesfound in the formulae as provided herein.

In one aspect, compounds described herein are prepared according toScheme 1 (where R⁴, R⁸, Z and A are as described herein).

A substituted 2-methyl-methyl benzoate of structure 1-I is brominated toprovide a compound of structure 1-II. Displacement of the bromide incompound 1-II with a nucleophile HZ-R⁸ in the presence of a baseprovides a compound of structure 1-III. The ester moiety of compound1-III is reduced to an alcohol and reaction of the benzyl alcohol withphosphorous tribromide furnishes the compound 1-IV. Reaction of compound1-IV with compound 1-V provides compound 1-VI via bromide displacement.Other heterocyclic rings (see description of ring A described herein)may be used in place of the pyrazole in compound 1-V. The nitrile moietyin compound 1-VI is converted to a tetrazolyl moiety upon reaction withTMS azide in the presence of dibutyl tin oxide. Removal of anyprotecting groups then provides a compound of Formula (I).

In one aspect, the compounds of Formula (I) are prepared as outlined inScheme 2:

Displacement of the bromide in compound 1-IV with cyanide provides thenitrile of structure 2-II. Conversion of the nitrile moiety of compound2-II to an imidate using standard procedures provides compound 2-IIIwhich is then cyclized in the presence of triethylethane-1,1,2-tricarboxylate to provide the pyrimidinyl compound ofstructure 2-IV. In one embodiment, the compound 2-IV is optionallyallowed to react with phosphorous oxy chloride to provide a compound2-V. In one aspect, the ester of compound 2-V is hydrolyzed to providecompound 2-VI. In another aspect, compound 2-V is reacted with anucleophile (R^(A)—H) and then the ester is hydrolyzed to providecompound 2-VI.

In one aspect, the compounds of Formula (I) are prepared as outlined inScheme 3:

Reaction of the nitrile of structure 2-II with hydroxylamine provides aN-hydroxycarbamimidoylmethyl compound of structure 3-II. Cyclization of3-II in the presence of tert-butyl ethyl malonate provides theoxadiazolyl acetic acid compound 3-III. Ester hydrolysis then furnishesa compound of Formula (I).

In one aspect, compounds of Formula (I) are prepared as depicted inScheme 4:

The benzyl bromide of structure 1-IV is coupled with a potassiumtrifluoroborate heteroaryl (prepared using methods known in the art,see, e.g., Vedejs E. et al., J. Am. Chem. Soc., 1999, 121, 2460) toprovide compound 4-II which upon ester hydrolysis provides a compound ofFormula (I). Alternatively, boronic acids or boronic esters ofheteroaryls can be used in place of the potassium trifluoroborateheteroaryl to provide compounds of Formula (I).

In one aspect, compounds described herein are prepared according toScheme 5.

Heteroaryls of structure 5-I are reacted with fluorobenzaldehydes ofstructure 5-II under SN_(AR) conditions to provide diarylethers ofstructure 5-III. Other methods of forming diaryl ethers are known, suchas metal mediated reactions, including but not limited to the UlmanEther synthesis, Chan-Lam coupling, and Buchwald-Hartwig synthesis (D.Ma, Q. Cai, Org. Lett., 2003, 5, 3799-3802; C. G. Bates, et al., Org.Lett., 2002, 4, 2803-2806; C. H. Burgos, et al., Angew. Chem. Int. Ed.,2006, 45, 4321-4326; C. H. Burgos, et al., Angew. Chem. Int. Ed., 2006,45, 4321-4326; D. M. T. Chan, et al., Tetrahedron Lett., 1998, 39,2933-2936; Z. Liu, R. C. Larock, J. Org. Chem., 2006, 71, 3198-3209;Y.-J. Chen, H.-H. Chen, Org. Lett., 2006, 8, 5609-5612; F. Li, Q. etal., Org. Lett., 2003, 5, 2169-2171; D. A. Evans, et al., TetrahedronLetters, 1998, 39, 2937-2940; C.-E. Yeom, et al., Synlett, 2007,146-150). The aldehyde moiety of diaryl ethers of structure 5-III isreduced to the alcohol to provide compounds of structure 5-IV. In oneaspect the aldehyde group of compounds of structure 5-III is reducedwith sodium borohydride. Benzyl alcohols of structure 5-IV are thenconverted into benzyl halides of structure 5-V. In one aspect, benzylalcohols of structure 5-IV are treated with PBr₃ to provide benzylbromides of structure 5-V. Benzyl bromides of structure 5-V are reactedwith thiols of structure R⁸—SH, where R⁸ is as described herein. Inanother aspect, benzyl bromides of structure 5-V are reacted withhydroxy compounds of structure R⁸—OH, where R⁸ is as described herein.Hydrolysis of ester group of compounds of structure 5-VI providescompounds of structure 5-VII. In one aspect, the compound of Formula (I)has the structure of 5-VI. In one aspect, the compound of Formula (I)has the structure of 5-VII. In another aspect, compounds of structure5-VI or 5-VII are treated with oxidizing agents to provide thecorresponding sulfoxide and sulfone compounds. In one aspect, theoxidizing agent is meta-chloroperoxybenzoic acid.

In cases where R⁴ is a halide or other leaving group, metal mediatedcoupling reactions may be used to introduce other groups at R⁴. Metalmediated coupling reactions include, but are not limited to Suzukireactions, Stille cross couplings, Negishi couplings, Kumada couplings,Ullmann reactions, Hiyama Coupling, and variants thereof(Metal-Catalyzed Cross-Coupling Reactions, Armin de Meijere (Editor),François Diederich (Editor), John Wiley & Sons; 2nd edition, 2004;Özdemir, et al., Tetrahedron, 2005, 61, 9791-9798; Ackermann, et al.,Org. Lett., 2006, 8, 3457-3460; Blakey, et al., J. Am. Chem. Soc., 2003,125, 6046-6047; Dai, et al., Org. Lett., 2004, 6, 221-224; Yoshikai, etal, J. Am. Chem. Soc., 2005, 127, 17978-17979; Tang, et al, J. Org.Chem., 2006, 71, 2167-2169; Murata, et al., Synthesis, 2001, 2231-2233).

In one aspect, R⁴ in Scheme 5 is a nitro group (—NO₂). Reduction of thenitro group provides the amino (R⁴ is —NH₂). Reaction conditions for thereduction of nitrobenzenes to anilines include, but are not limited to,catalytic hydrogenation using palladium-on-carbon (Bavin, P. M. G.(1973). Org. Synth.; Coll. Vol. 5: 30), platinum oxide, or Raney nickel(Allen, C. F. H.; VanAllan, J. (1955)). Org. Synth.; Coll. Vol. 3: 63),iron in acidic media (Fox, B. A.; Threlfall, T. L. (1973). Org. Synth.;Coll. Vol. 5: 346), sodium hydrosulfite (Redemann, C. T.; Redemann, C.E. (1955). Org. Synth.; Coll. Vol. 3: 69), sodium sulfide (or hydrogensulfide and base), tin(II) chloride, titanium(III) chloride, and zinc.

Amines (R⁴ is —NH₂) are reacted with a variety of agents, such as, butnot limited to alkyl halides, benzyl halides, acyl halides,chloroformates, isocyanates, sulfonyl halides, and the like, to providecompounds of Formula (I).

In one aspect, amines (R⁴ is —NH₂) amine are reacted with alkyl halides,or benzyl halides or other alkylating agents. In one embodiment, aminesare treated with acyl halides to provide amides.

In some embodiments, amines (R⁴ is —NH₂) are reacted with, but notlimited to, a carboxylic acid and coupling reagent such as EDC, DCC,BOP, HATU or the like, or a carboxylic acid activated ester or an acidhalide, alkylchloroformate, arylchloroformate, benzylchloroformate,alkylisocyanate, benzylisocyanate, arylisocyanate, alkylsulfonylchloride, arylsulfonyl chloride, heteroarylsulfonyl chloride, or thelike in dichloromethane, dichloroethane, tetrahydrofuran,dimethoxyethane or the like in the presence of a hindered base such astriethylamine, diisopropylethylamine, N-methylmorpholine, pyridine orthe like, to afford compounds of Formula (I).

Carbamates from the amine (i.e. R⁴) are prepared by reacting withchloroformates. Methods for the preparation of carbamates are known,such as described herein or in reference texts such as, but not limitedto, Greene, T. W. and Wuts, P. G. M “Protective Groups in OrganicSynthesis”, 3rd Edition, p. 549, New York: Wiley, 1999. Ureas areprepared by reacting amines with isocyanates. Common methods for thesynthesis of isocyanates include the Curtius rearrangement of acylazides and the Lossen rearrangement of hydroxamic acids. The synthesisof ureas include the following procedures: C. Han, J. A. Porco, Jr, Org.Lett., 2007, 9, 1517-1520; H. Lebel, O. Leogane, Org. Lett., 2006, 8,5717-5720; M. B. Bertrand, J. P. Wolfe, Tetrahedron, 2005, 61,6447-6459; M. McLaughlin, M. Palucki, I. W. Davies, Org. Lett., 2006, 8,3311-3314; J. A. Fritz, J. S, Nakhla, J. P. Wolfe, Org. Lett., 2006, 8,2531-2534; L. Marinescu, J. Thinggaard, I. B. Thomsen, M. Bols, J. Org.Chem., 2003, 68, 9453-9455; S.-H. Lee, H. Matsushita, B. Clapham, K. D.Janda, Tetrahedron, 2004, 60, 3439-3443. Reaction of amines withsulfonyl chlorides provides sulfonamides.

Other methods for the synthesis of compounds of Formula (I) arecontemplated.

In one aspect, compounds of Formula (I) are synthesized as outlined inthe Examples.

Further Forms of Compounds

In certain embodiments, compounds of Formula (I) are prepared as apharmaceutically acceptable acid addition salt (which is a type of apharmaceutically acceptable salt) by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid,including, but not limited to, inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acidmetaphosphoric acid, and the like; and organic acids such as aceticacid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaricacid, trifluoroacetic acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid,1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, and muconic acid. In certain embodiments, compoundsof Formula (I) are prepared as N-oxides.

By “pharmaceutically acceptable,” as used herein, refers to a material,such as a carrier or diluent, which does not abrogate the biologicalactivity or properties of the compound, and is relatively nontoxic,i.e., the material may be administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound of Formula (I) with acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid and the like. Pharmaceutically acceptable salts are alsoobtained by reacting a compound of Formula (I) with a base to form asalt such as an ammonium salt, an alkali metal salt, such as a sodium ora potassium salt, an alkaline earth metal salt, such as a calcium or amagnesium salt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts withamino acids such as arginine, lysine, and the like. In some embodiments,the pharmaceutically acceptable salt of the compound of Formula (I) is asodium salt.

In other embodiments, compounds of Formula (I) are prepared as apharmaceutically acceptable salts by reacting the free acid form of thecompound with a pharmaceutically acceptable inorganic or organic base,including, but not limited to organic bases such as ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine, andthe like, or with an inorganic base such as aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, andthe like.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and areoptionally formed during the process of crystallization withpharmaceutically acceptable solvents such as water, ethanol, and thelike. Hydrates are formed when the solvent is water, or alcoholates areformed when the solvent is alcohol. Solvates of compounds of Formula (I)are conveniently prepared or formed during the processes describedherein. By way of example only, hydrates of compounds of Formula (I) areconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents including, but not limited to,dioxane, tetrahydrofuran, ethanol, or methanol. In addition, certaincompounds provided herein exist in unsolvated as well as solvated forms.In general, the solvated forms are considered equivalent to theunsolvated forms for the purposes of the compounds and methods providedherein.

In yet other embodiments, the compounds of Formula (I) are prepared invarious forms, including but not limited to, amorphous forms, milledforms and nano-particulate forms. In addition, compounds of Formula (I)include crystalline forms, also known as polymorphs. Polymorphs includethe different crystal packing arrangements of the same elementalcomposition of a compound. Polymorphs usually have different X-raydiffraction patterns, infrared spectra, melting points, density,hardness, crystal shape, optical and electrical properties, stability,and solubility. Various factors such as the recrystallization solvent,rate of crystallization, and storage temperature may cause a singlecrystal form to dominate.

In some embodiments, compounds of Formula (I) are prepared as prodrugs.A “prodrug” refers to an agent that is converted into the parent drug invivo. Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. An example, without limitation, of a prodrug wouldbe a compound of Formula (I) which is administered as an ester (the“prodrug”) to facilitate transmittal across a cell membrane where watersolubility is detrimental to mobility but which then is metabolicallyhydrolyzed to the carboxylic acid, the active entity, once inside thecell where water-solubility is beneficial. A further example of aprodrug might be a short peptide (polyaminoacid) bonded to an acid groupwhere the peptide is metabolized to reveal the active moiety.

Prodrugs are generally drug precursors that, following administration toa subject and subsequent absorption, are converted to an active, or amore active species via some process, such as conversion by a metabolicpathway. Some prodrugs have a chemical group present on the prodrug thatrenders it less active and/or confers solubility or some other propertyto the drug. Once the chemical group has been cleaved and/or modifiedfrom the prodrug the active drug is generated. Prodrugs are often usefulbecause, in some situations, they are easier to administer than theparent drug. In certain embodiments, the prodrug of a compound describedherein is bioavailable by oral administration whereas the parent is not.Furthermore, in some embodiments, the prodrug of a compound describedherein has improved solubility in pharmaceutical compositions over theparent drug.

In other embodiments, prodrugs are designed as reversible drugderivatives, for use as modifiers to enhance drug transport tosite-specific tissues. In specific embodiments, the design of prodrugsto date is to increase the effective water solubility of the therapeuticcompound for targeting to regions where water is the principal solvent.Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al.,Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom.,6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37,87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988);Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V.Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S.Symposium Series; and Edward B. Roche, Bioreversible Carriers in DrugDesign, American Pharmaceutical Association and Pergamon Press, 1987.

Additionally, prodrug derivatives of compounds of Formula (I) areprepared, if desired (e.g., for further details see Saulnier et al.,(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). Byway of example only, in one aspect appropriate prodrugs are prepared byreacting a non-derivatized compound of Formula (I) with a suitablecarbamylating agent, such as, but not limited to,1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or thelike. Prodrug forms of the herein described compounds, wherein theprodrug is metabolized in vivo to produce a derivative as set forthherein are included within the scope of the claims. Indeed, some of theherein-described compounds are a prodrug for another derivative oractive compound.

In some embodiments, sites on the aromatic ring portion of compounds ofFormula (I) are susceptible to various metabolic reactions Thereforeincorporation of appropriate substituents on the aromatic ringstructures will reduce, minimize or eliminate this metabolic pathway. Inspecific embodiments, the appropriate substituent to decrease oreliminate the susceptibility of the aromatic ring to metabolic reactionsis, by way of example only, a halogen, or an alkyl group.

In another embodiment, the compounds described herein are labeledisotopically (e.g. with a radioisotope) or by another other means,including, but not limited to, the use of chromophores or fluorescentmoieties, bioluminescent labels, or chemiluminescent labels.

In yet another embodiment, the compounds of Formula (I) possess one ormore stereocenters and each center exists independently in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. In certain embodiments, compounds ofFormula (I) are prepared as their individual stereoisomers by reacting aracemic mixture of the compound with an optically active resolving agentto form a pair of diastereoisomeric compounds, separating thediastereomers and recovering the optically pure enantiomers. In someembodiments, resolution of enantiomers is carried out using covalentdiastereomeric derivatives of the compounds described herein. In otherembodiments, dissociable complexes are utilized (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and are, in specific embodiments, separated by taking advantage of thesedissimilarities. In these embodiments, the diastereomers are separatedby chiral chromatography or by separation/resolution techniques basedupon differences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatdoes not result in racemization. Jean Jacques, Andre Collet, Samuel H.Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons,Inc., 1981.

Additionally, in certain embodiments, the compounds provided hereinexist as geometric isomers. The compounds and methods provided hereininclude all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the appropriate mixtures thereof. In someembodiments, the compounds described herein exist as tautomers. Alltautomers are intended to be within the scope of the molecular formulasdescribed herein. In additional embodiments of the compounds and methodsprovided herein, mixtures of enantiomers and/or diastereoisomers,resulting from a single preparative step, combination, orinterconversion are envisioned.

Certain Terminology

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Unlessotherwise indicated, conventional methods of mass spectroscopy, NMR,HPLC, protein chemistry, biochemistry, recombinant DNA techniques andpharmacology are employed. In this application, the use of “or” or “and”means “and/or” unless stated otherwise. Furthermore, use of the term“including” as well as other forms, such as “include”, “includes,” and“included,” is not limiting.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylmoiety may be a saturated alkyl group (which means that it does notcontain any carbon-carbon double bonds or carbon-carbon triple bonds) orthe alkyl moiety may be an unsaturated alkyl group (which means that itcontains at least one carbon-carbon double bond or carbon-carbon triplebond). The alkyl moiety, whether saturated or unsaturated, may bebranched or straight chain.

The “alkyl” moiety may have 1 to 10 carbon atoms (whenever it appearsherein, a numerical range such as “1 to 10” refers to each integer inthe given range; e.g., “1 to 10 carbon atoms” means that the alkyl groupmay consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., upto and including 10 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated). The alkyl group of the compounds described herein may bedesignated as “C₁-C₆alkyl” or similar designations. By way of exampleonly, “C₁-C₆alkyl” indicates that there are one, two, three, four, five,or six carbon atoms in the alkyl chain. In one aspect, the alkyl isselected from the group consisting of methyl, ethyl, propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groupsinclude, but are in no way limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tertiary butyl, pentyl, hexyl, allyl, but-2-enyl,but-3-enyl, and the like. In one aspect, an alkyl is a C₁-C₆alkyl.Depending on the structure, a alkyl group can be a monoradical or adiradical (i.e. alkylene).

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

The term “alkylamine” refers to the —N(alkyl)_(x) Hy group, where x andy are selected from the group x=11, y=11 and x=2, y=0. In someembodiments, when x=2 and y=0, the alkyl groups taken together with thenitrogen atom to which they are attached form a cyclic ring system.

An “amide” is a chemical moiety with formula —C(═O)NHR or —NHC(═O)R,where R is selected from the group consisting of alkyl, cycloalkyl,aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic(bonded through a ring carbon). An amide may be an amino acid or apeptide molecule attached to a compound of Formula (I), thereby forminga prodrug. Any amine, or carboxyl side chain on the compounds describedherein is optionally amidified, as desired. See, e.g., Greene and Wuts,Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wiley & Sons,New York, N.Y., 1999, is incorporated herein by reference for suchdisclosure.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2π electrons, where n is an integer.Aromatic rings can be formed from five, six, seven, eight, nine, ten, ormore than ten atoms. Aromatics are a substituted or unsubstituted. Theterm “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl)and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups(e.g., pyridine). The term includes monocyclic or fused-ring polycyclic(i.e., rings which share adjacent pairs of carbon atoms) groups.

The term “carbocyclic” refers to a ring or ring system where the atomsforming the backbone of the ring are all carbon atoms. The term thusdistinguishes carbocyclic from heterocyclic rings in which the ringbackbone contains at least one atom which is different from carbon.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings are formed byfive, six, seven, eight, nine, or more than nine carbon atoms. Arylgroups are a substituted or unsubstituted. In one aspect, an aryl is aphenyl or a naphthalenyl. Depending on the structure, an aryl group canbe a monoradical or a diradical (i.e., an arylene group). In one aspect,an aryl is a C₆-C₁₀aryl.

The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic,non-aromatic radical, wherein each of the atoms forming the ring (i.e.skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, orpartially unsaturated. Cycloalkyls may be fused with an aromatic ring,and the point of attachment is at a carbon that is not an aromatic ringcarbon atom. Cycloalkyl groups include groups having from 3 to 10 ringatoms. Illustrative examples of cycloalkyl groups include, but are notlimited to, the following moieties:

and the like. In some embodiments, cycloalkyl groups are selected fromamong cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. In some embodiments, bicyclic cycloalkyl groups are selectedfrom among indanyl, indenyl, and 1,2,3,4-tetrahydronaphthalenyl.Cycloalkyl groups may be substituted or unsubstituted. Depending on thestructure, a cycloalkyl group can be a monoradical or a diradical (i.e.,an cycloalkylene group, such as, but not limited to,cyclopropan-1,1-diyl, cyclobutan-1,1-diyl, cyclopentan-1,1-diyl,cyclohexan-1,1-diyl, cycloheptan-1,1-diyl, and the like).

The term “ester” refers to a chemical moiety with formula —COOR, where Ris selected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heteroalicyclic (bondedthrough a ring carbon). Any hydroxy, or carboxyl side chain on thecompounds described herein is esterified, if desired. Examples ofprocedures and specific groups to make such esters are found in sourcessuch as Greene and Wuts, Protective Groups in Organic Synthesis, 3^(rd)Ed., John Wiley & Sons, New York, N.Y., 1999.

The term “halo” or, alternatively, “halogen” or “halide” means fluoro,chloro, bromo or iodo.

The term “haloalkyl” refers to an alkyl group in which one or morehydrogen atoms are replaced by one or more halide atoms. In one aspect,a haloalkyl is a C₁-C₄haloalkyl.

The term “fluoroalkyl” refers to a alkyl in which one or more hydrogenatoms are replaced by a fluorine atom. In one aspect, a fluoralkyl is aC₁-C₄fluoroalkyl.

The term “heteroalkyl” refers to an alkyl group in which one or moreskeletal atoms of the alkyl are selected from an atom other than carbon,e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Inone aspect, a heteroalkyl is a C₁-C₆ heteroalkyl.

The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings(also known as heteroaryls) and heterocycloalkyl rings (also known asheteroalicyclic groups) containing one to four heteroatoms in thering(s), where each heteroatom in the ring(s) is selected from O, S andN, wherein each heterocyclic group has from 4 to 10 atoms in its ringsystem, and with the proviso that the any ring does not contain twoadjacent O or S atoms. Non-aromatic heterocyclic groups (also known asheterocycloalkyls) include groups having only 3 atoms in their ringsystem, but aromatic heterocyclic groups must have at least 5 atoms intheir ring system. The heterocyclic groups include benzo-fused ringsystems. An example of a 3-membered heterocyclic group is aziridinyl. Anexample of a 4-membered heterocyclic group is azetidinyl. An example ofa 5-membered heterocyclic group is thiazolyl. An example of a 6-memberedheterocyclic group is pyridyl, and an example of a 10-memberedheterocyclic group is quinolinyl. Examples of non-aromatic heterocyclicgroups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of aromatic heterocyclic groups are imidazolyl,pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl,isoxazolyl, oxadiazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,thiadiazolyl, furazanyl, oxadiazolyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, isoindolyl, pteridinyl, purinyl, benzofurazanyl,benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, and furopyridinyl. The foregoing groups may beC-attached or N-attached where such is possible. For instance, a groupderived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). Further, a group derived from imidazole may beimidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems. Non-aromatic heterocycles may besubstituted with one or two oxo (═O) moieties, such as pyrrolidin-2-one.The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. In one aspect, a heteroaryl is a monocyclicor bicyclic heteroaryl. Illustrative examples of heteroaryl groupsinclude the following moieties:

and the like. Monocyclic heteroaryls include imidazolyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl,oxadiazolyl, thiazolyl, isothiazolyl, oxazolyl, isothiazolyl, pyrrolyl,thiadiazolyl, furazanyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl,pyridazinyl, and triazinyl. In one aspect, monocyclic heteroarylsinclude imidazolyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, oxazolyl,isothiazolyl, pyrrolyl, thiadiazolyl, furazanyl, and oxadiazolyl. In oneaspect, monocyclic heteroaryls include pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, and triazinyl. Bicyclic heteroaryls includequinolinyl, isoquinolinyl, quinazolinyl, quinoxazolinyl, naphthyridinyl,indolyl, indazolyl, benzoxazolyl, benzisoxazolyl, oxadiazolyl,benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl,pyridopyrimidinyl, pyrazolopyrimidinyl, azaindolyl, pyrazolopyridinyl,thiazolopyrimidinyl, thiazolopyridinyl, pyridothienyl, pyrimidiothienyland pyrrolopyrimidinyl. In one aspect, a heteroaryl contains 0-4 Natoms. In one aspect, a heteroaryl contains 0-3 N atoms. In anotheraspect, a heteroaryl contains 1-3 N atoms. In another aspect, aheteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms. In oneaspect, the heteroaryl is a C₁-C₁₀heteroaryl. In some cases, theheteroaryl includes at least one N atom in the ring. In one aspect,monocyclic heteroaryl is a C₁-C₅heteroaryl. In one aspect, bicyclicheteroaryl is a C₅-C₁₀heteroaryl. Depending on the structure, aheteroaryl group can be a monoradical or a diradical (i.e. aheteroarylene). Heteroarylene includes heteroarylene groups in which thetwo points of attachment to the rest of the molecule are in a 1,2 (i.e.ortho) or 1,3 (i.e. meta) or 1,4 (i.e. para) position on the ring.

A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkylgroup that includes at least one heteroatom selected from nitrogen,oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl.Illustrative examples of heterocycloalkyl groups, also referred to asnon-aromatic heterocycles, include:

and the like. In some embodiments, the heterocycloalkyl is selected fromoxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, and indolinyl. The term heteroalicyclicalso includes all ring forms of the carbohydrates, including but notlimited to the monosaccharides, the disaccharides and theoligosaccharides. In one aspect, a heterocycloalkyl is aC₂-C₁₀heterocycloalkyl. In another aspect, a heterocycloalkyl is aC₄-C₁₀heterocycloalkyl. In one aspect, a heterocycloalkyl contains 0-2 Natoms. In another aspect, a heterocycloalkyl contains 0-2 N atoms, 0-2 Oatoms or 0-1 S atoms.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure. In one aspect, when a group describedherein is a bond, the referenced group is absent thereby allowing a bondto be formed between the remaining identified groups.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

As used herein, “carboxylic acid bioisostere” refers to a functionalgroup or moiety that exhibits similar physical and/or chemicalproperties as a carboxylic acid moiety. In one aspect, a carboxylic acidbioisostere has similar biological properties to that of a carboxylicacid group. A compound with a carboxylic acid moiety can have thecarboxylic acid moiety exchanged with a carboxylic acid bioisostere andhave similar physical and/or biological properties when compared to thecarboxylic acid-containing compound. For example, in one embodiment, acarboxylic acid bioisostere would ionize at physiological pH to roughlythe same extent as a carboxylic acid group. Examples of bioisoteres of acarboxylic acid include, but are not limited to,

and the like.

The term “membered ring” includes any cyclic structure. The term“membered” is meant to denote the number of skeletal atoms thatconstitute the ring. Thus, for example, cyclohexyl, pyridinyl, pyranyland thiopyranyl are 6-membered rings and cyclopentyl, pyrrolyl, furanyl,and thienyl are 5-membered rings.

The term “substituted or unsubstituted” means that the referenced groupmay be optionally substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone,cyano, halo, nitro, haloalkyl, fluoroalkyl, and amino, including mono-and di-substituted amino groups, and the protected derivatives thereof.By way of example an optional substituent may be halide, —CN, —NO₂, orL_(s)R_(s), wherein each L_(s) is independently selected from a bond,—O—, —C(═O)—, —C(═O)O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —NHC(═O)—,—C(═O)NH—, S(═O)₂NH—, —NHS(═O)₂, —OC(═O)NH—, —NHC(═O)O—, or—(C₁-C₆alkyl)-; and each R_(s) is selected from H, alkyl, fluoroalkyl,heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. Theprotecting groups that may form the protective derivatives of the abovesubstituents may be found in sources such as Greene and Wuts, above. Insome embodiments, optional substituents are selected from halogen, —CN,—NH₂, —OH, —N(CH₃)₂, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In one aspect, an optional substituent is halogen, —CN, —NH₂, —OH,—N(CH₃)₂, —NH(CH₃), —CH₃, —CF₃, —OCH₃, or —OCF₃. In some embodiments,substituted groups are substituted with 1 or more of the aforementionedgroups. In some embodiments, substituted groups are substituted with 1of the aforementioned groups.

In certain embodiments, the compounds presented herein possess one ormore stereocenters and each center independently exists in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. Stereoisomers are obtained, if desired, bymethods such as, the separation of stereoisomers by chiralchromatographic columns.

The methods and formulations described herein include the use ofN-oxides (if appropriate), crystalline forms (also known as polymorphs),or pharmaceutically acceptable salts of compounds having the structureof Formula (I), as well as active metabolites of these compounds havingthe same type of activity. In some situations, compounds may exist astautomers. All tautomers are included within the scope of the compoundspresented herein. In specific embodiments, the compounds describedherein exist in solvated forms with pharmaceutically acceptable solventssuch as water, ethanol, and the like. In other embodiments, thecompounds described herein exist in unsolvated form.

Certain Pharmaceutical and Medical Terminology

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “modulate,” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator,” as used herein, refers to a molecule thatinteracts with a target either directly or indirectly. The interactionsinclude, but are not limited to, the interactions of an agonist, partialagonist, an inverse agonist and antagonist. In one embodiment, amodulator is an antagonist.

The term “agonist,” as used herein, refers to a molecule such as acompound, a drug, an enzyme activator or a hormone modulator that bindsto a specific receptor and triggers a response in the cell. An agonistmimics the action of an endogenous ligand (such as prostaglandin,hormone or neurotransmitter) that binds to the same receptor.

The term “antagonist,” as used herein, refers to a molecule such as acompound, which diminishes, inhibits, or prevents the action of anothermolecule or the activity of a receptor site. Antagonists include, butare not limited to, competitive antagonists, non-competitiveantagonists, uncompetitive antagonists, partial agonists and inverseagonists.

Competitive antagonists reversibly bind to receptors at the same bindingsite (active site) as the endogenous ligand or agonist, but withoutactivating the receptor.

Non-competitive antagonists (also known as allosteric antagonists) bindto a distinctly separate binding site from the agonist, exerting theiraction to that receptor via the other binding site. Non-competitiveantagonists do not compete with agonists for binding. The boundantagonists may result in a decreased affinity of an agonist for thatreceptor, or alternatively may prevent conformational changes in thereceptor required for receptor activation after the agonist binds.

Uncompetitive antagonists differ from non-competitive antagonists inthat they require receptor activation by an agonist before they can bindto a separate allosteric binding site.

Partial agonists are defined as drugs which, at a given receptor, mightdiffer in the amplitude of the functional response that they elicitafter maximal receptor occupancy. Although they are agonists, partialagonists can act as a competitive antagonist if co-administered with afull agonist, as it competes with the full agonist for receptoroccupancy and producing a net decrease in the receptor activationobserved with the full agonist alone.

An inverse agonist can have effects similar to an antagonist, but causesa distinct set of downstream biological responses. Constitutively activereceptors which exhibit intrinsic or basal activity can have inverseagonists, which not only block the effects of binding agonists like aclassical antagonist, but inhibit the basal activity of the receptor.

The term “PGD₂-dependent”, as used herein, refers to conditions ordisorders that would not occur, or would not occur to the same extent,in the absence of PGD₂.

The term “PGD₂-mediated”, as used herein, refers to refers to conditionsor disorders that might occur in the absence of PGD₂ but can occur inthe presence of PGD₂.

The term “asthma” as used herein refers to any disorder of the lungscharacterized by variations in pulmonary gas flow associated with airwayconstriction of whatever cause (intrinsic, extrinsic, or both; allergicor non-allergic). The term asthma may be used with one or moreadjectives to indicate cause.

The term “rhinitis” as used herein refers to any disorder of the nose inwhich there is inflammation of the mucous lining of the nose by whatevercause (intrinsic, extrinsic or both; allergic or non-allergic).

The term “bone disease,’ as used herein, refers to a disease orcondition of the bone, including, but not limited to, inapproriate boneremodeling, loss or gain, osteopenia, osteomalacia, osteofibrosis, andPaget's disease.

The term “cardiovascular disease,” as used herein refers to diseasesaffecting the heart or blood vessels or both, including but not limitedto: arrhythmia (atrial or ventricular or both); atherosclerosis and itssequelae; angina; cardiac rhythm disturbances; myocardial ischemia;myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke;peripheral obstructive arteriopathy of a limb, an organ, or a tissue;reperfusion injury following ischemia of the brain, heart or other organor tissue; endotoxic, surgical, or traumaticshock; hypertension,valvular heart disease, heart failure, abnormal blood pressure; shock;vasoconstriction (including that associated with migraines); vascularabnormality, inflammation, insufficiency limited to a single organ ortissue.

The term “cancer,” as used herein refers to an abnormal growth of cellswhich tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). The types of cancer include, but is not limitedto, solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, lymhatic tissue (lymphoma), ovary,pancreas or other endocrine organ (thyroid), prostate, skin (melanoma)or hematological tumors (such as the leukemias).

The term “carrier,” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The term “dermatological disorder,” as used herein refers to a skindisorder. Such dermatological disorders include, but are not limited to,proliferative or inflammatory disorders of the skin such as, atopicdermatitis, bullous disorders, collagenoses, contact dermatitis eczema,Kawasaki Disease, rosacea, Sjogren-Larsso Syndrome, urticaria.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. Diluents can also be used tostabilize compounds because they can provide a more stable environment.Salts dissolved in buffered solutions (which also can provide pH controlor maintenance) are utilized as diluents in the art, including, but notlimited to a phosphate buffered saline solution.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case may be determinedusing techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The terms “fibrosis” or “fibrosing disorder,” as used herein, refers toconditions that follow acute or chronic inflammation and are associatedwith the abnormal accumulation of cells and/or collagen and include butare not limited to fibrosis of individual organs or tissues such as theheart, kidney, joints, lung, or skin, and includes such disorders asidiopathic pulmonary fibrosis and cryptogenic fibrosing alveolitis.

The term “iatrogenic” means a PGD₂-dependent or PGD₂-mediated condition,disorder, or disease created or worsened by medical or surgical therapy.

The term “inflammatory disorders” refers to those diseases or conditionsthat are characterized by one or more of the signs of pain, heat,redness, swelling, and loss of function (temporary or permanent).Inflammation takes many forms and includes, but is not limited to,inflammation that is one or more of the following: acute, adhesive,atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated,exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic,hypertrophic, interstitial, metastatic, necrotic, obliterative,parenchymatous, plastic, productive, proliferous, pseudomembranous,purulent, sclerosing, seroplastic, serous, simple, specific, subacute,suppurative, toxic, traumatic, and/or ulcerative. Inflammatory disordersfurther include, without being limited to those affecting the bloodvessels (polyarteritis, temporal arteritis); joints (arthritis:crystalline, osteo-, psoriatic, reactive, rheumatoid, Reiter's);gastrointestinal tract (colitis); skin (dermatitis); or multiple organsand tissues (systemic lupus erythematosus).

The term “immunological disorders” refers to those diseases orconditions that are characterized by inappropriate or deleteriousresponse to an endogenous or exogenous antigen that may result incellular dysfunction or destruction and consequently dysfunction ordestruction of an organ or tissue and which may or may not beaccompanied by signs or symptoms of inflammation.

The terms “kit” and “article of manufacture” are used as synonyms.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulphydryl groups. Metabolites of the compounds disclosed herein areoptionally identified either by administration of compounds to a hostand analysis of tissue samples from the host, or by incubation ofcompounds with hepatic cells in vitro and analysis of the resultingcompounds.

The terms “neurogenerative disease” or “nervous system disorder,” asused herein, refers to conditions that alter the structure or functionof the brain, spinal cord or peripheral nervous system, including butnot limited to Alzheimer's Disease, cerebral edema, cerebral ischemia,multiple sclerosis, neuropathies, Parkinson's Disease, those found afterblunt or surgical trauma (including post-surgical cognitive dysfunctionand spinal cord or brain stem injury), as well as the neurologicalaspects of disorders such as degenerative disk disease and sciatica. Theacronym “CNS” refers to disorders of the central nervous system, i.e.,brain and spinal cord.

The terms “ocular disease” or “ophthalmic disease,” as used herein,refer to diseases which affect the eye or eyes and potentially thesurrounding tissues as well. Ocular or ophthalmic diseases include, butare not limited to, conjunctivitis, retinitis, scleritis, uveitis,allergic conjuctivitis, vernal conjunctivitis, papillary conjunctivitis.

The term “interstitial cystitis” refers to a disorder characterized bylower abdominal discomfort, frequent and sometimes painful urinationthat is not caused by anatomical abnormalites, infection, toxins, traumaor tumors.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula (I) and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of Formula (I) and a co-agent, areadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific intervening time limits,wherein such administration provides effective levels of the twocompounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of three or more activeingredients.

The term “pharmaceutical composition” refers to a mixture of a compoundof Formula (I) with other chemical components, such as carriers,stabilizers, diluents, dispersing agents, suspending agents, thickeningagents, and/or excipients. The pharmaceutical composition facilitatesadministration of the compound to an organism. Multiple techniques ofadministering a compound exist in the art including, but not limited to:intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary andtopical administration.

The term “respiratory disease,” as used herein, refers to diseasesaffecting the organs that are involved in breathing, such as the nose,throat, larynx, eustachian tubes, trachea, bronchi, lungs, relatedmuscles (e.g., diaphram and intercostals) and nerves. Respiratorydiseases include, but are not limited to, asthma, adult respiratorydistress syndrome and allergic (extrinsic) asthma, non-allergic(intrinsic) asthma, acute severe asthma, chronic asthma, clinicalasthma, neutrophilic asthma, nocturnal asthma, allergen-induced asthma,aspirin-sensitive asthma, exercise-induced asthma, isocapnichyperventilation, child-onset asthma, adult-onset asthma, cough-variantasthma, occupational asthma, steroid-resistant asthma, seasonal asthma,seasonal allergic rhinitis, perennial allergic rhinitis, chronicobstructive pulmonary disease, including chronic bronchitis oremphysema, pulmonary hypertension, interstitial lung fibrosis and/orairway inflammation and cystic fibrosis, and hypoxia.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one embodiment, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying causes of symptoms, inhibiting the disease or condition,e.g., arresting the development of the disease or condition, relievingthe disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Routes of Administration Suitable routes of administration include, butare not limited to, oral, intravenous, rectal, aerosol, parenteral,ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal,and topical administration. In addition, by way of example only,parenteral delivery includes intramuscular, subcutaneous, intravenous,intramedullary injections, as well as intrathecal, directintraventricular, intraperitoneal, intralymphatic, and intranasalinjections.

In certain embodiments, a compound as described herein is administeredin a local rather than systemic manner, for example, via injection ofthe compound directly into an organ, often in a depot preparation orsustained release formulation. In specific embodiments, long actingformulations are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Furthermore, in other embodiments, the drug is delivered in a targeteddrug delivery system, for example, in a liposome coated withorgan-specific antibody. In such embodiments, the liposomes are targetedto and taken up selectively by the organ. In yet other embodiments, thecompound as described herein is provided in the form of a rapid releaseformulation, in the form of an extended release formulation, or in theform of an intermediate release formulation. In yet other embodiments,the compound described herein is administered topically.

Pharmaceutical Composition/Formulation

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. In specific embodiments, pharmaceuticalcompositions are formulated in a conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Any pharmaceuticallyacceptable techniques, carriers, and excipients are used as suitable toformulate the pharmaceutical compositions described herein: Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999).

Provided herein are pharmaceutical compositions comprising a compound ofFormula (I) and a pharmaceutically acceptable diluent(s), excipient(s),or carrier(s). In certain embodiments, the compounds described areadministered as pharmaceutical compositions in which a compound ofFormula (I) is mixed with other active ingredients, as in combinationtherapy. Encompassed herein are all combinations of actives set forth inthe combination therapies section below and throughout this disclosure.In specific embodiments, the pharmaceutical compositions include one ormore compounds of Formula (I).

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula (I) with other chemical components, such ascarriers, stabilizers, diluents, dispersing agents, suspending agents,thickening agents, and/or excipients. In certain embodiments, thepharmaceutical composition facilitates administration of the compound toan organism. In some embodiments, practicing the methods of treatment oruse provided herein, therapeutically effective amounts of compounds ofFormula (I) are administered in a pharmaceutical composition to a mammalhaving a disease or condition to be treated. In specific embodiments,the mammal is a human. In certain embodiments, therapeutically effectiveamounts vary depending on the severity of the disease, the age andrelative health of the subject, the potency of the compound used andother factors. The compounds described herein are used singly or incombination with one or more therapeutic agents as components ofmixtures.

In one embodiment, one or more compounds of Formula (I) is formulated inan aqueous solution. In specific embodiments, the aqueous solution isselected from, by way of example only, a physiologically compatiblebuffer, such as Hank's solution, Ringer's solution, or physiologicalsaline buffer. In other embodiments, one or more compound of Formula (I)is formulated for transmucosal administration. In specific embodiments,transmucosal formulations include penetrants that are appropriate to thebarrier to be permeated. In still other embodiments wherein thecompounds described herein are formulated for other parenteralinjections, appropriate formulations include aqueous or nonaqueoussolutions. In specific embodiments, such solutions includephysiologically compatible buffers and/or excipients.

In another embodiment, compounds described herein are formulated fororal administration. Compounds described herein, including compounds ofFormula (I), are formulated by combining the active compounds with,e.g., pharmaceutically acceptable carriers or excipients. In variousembodiments, the compounds described herein are formulated in oraldosage forms that include, by way of example only, tablets, powders,pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries,suspensions and the like.

In certain embodiments, pharmaceutical preparations for oral use areobtained by mixing one or more solid excipient with one or more of thecompounds described herein, optionally grinding the resulting mixture,and processing the mixture of granules, after adding suitableauxiliaries, if desired, to obtain tablets or dragee cores. Suitableexcipients are, in particular, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol; cellulose preparations such as:for example, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Inspecific embodiments, disintegrating agents are optionally added.Disintegrating agents include, by way of example only, cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

In one embodiment, dosage forms, such as dragee cores and tablets, areprovided with one or more suitable coating. In specific embodiments,concentrated sugar solutions are used for coating the dosage form. Thesugar solutions, optionally contain additional components, such as byway of example only, gum arabic, talc, polyvinylpyrrolidone, carbopolgel, polyethylene glycol, and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Dyestuffs and/orpigments are also optionally added to the coatings for identificationpurposes. Additionally, the dyestuffs and/or pigments are optionallyutilized to characterize different combinations of active compounddoses.

In certain embodiments, therapeutically effective amounts of at leastone of the compounds described herein are formulated into other oraldosage forms. Oral dosage forms include push-fit capsules made ofgelatin, as well as soft, sealed capsules made of gelatin and aplasticizer, such as glycerol or sorbitol. In specific embodiments,push-fit capsules contain the active ingredients in admixture with oneor more filler. Fillers include, by way of example only, lactose,binders such as starches, and/or lubricants such as talc or magnesiumstearate and, optionally, stabilizers. In other embodiments, softcapsules, contain one or more active compound that is dissolved orsuspended in a suitable liquid. Suitable liquids include, by way ofexample only, one or more fatty oil, liquid paraffin, or liquidpolyethylene glycol. In addition, stabilizers are optionally added.

In other embodiments, therapeutically effective amounts of at least oneof the compounds described herein are formulated for buccal orsublingual administration. Formulations suitable for buccal orsublingual administration include, by way of example only, tablets,lozenges, or gels. In still other embodiments, the compounds describedherein are formulated for parental injection, including formulationssuitable for bolus injection or continuous infusion. In specificembodiments, formulations for injection are presented in unit dosageform (e.g., in ampoules) or in multi-dose containers. Preservatives are,optionally, added to the injection formulations. In still otherembodiments, the pharmaceutical composition of Formula (I) areformulated in a form suitable for parenteral injection as a sterilesuspensions, solutions or emulsions in oily or aqueous vehicles.Parenteral injection formulations optionally contain formulatory agentssuch as suspending, stabilizing and/or dispersing agents. In specificembodiments, pharmaceutical formulations for parenteral administrationinclude aqueous solutions of the active compounds in water-soluble form.In additional embodiments, suspensions of the active compounds areprepared as appropriate oily injection suspensions. Suitable lipophilicsolvents or vehicles for use in the pharmaceutical compositionsdescribed herein include, by way of example only, fatty oils such assesame oil, or synthetic fatty acid esters, such as ethyl oleate ortriglycerides, or liposomes. In certain specific embodiments, aqueousinjection suspensions contain substances which increase the viscosity ofthe suspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, the suspension contains suitable stabilizers oragents which increase the solubility of the compounds to allow for thepreparation of highly concentrated solutions. Alternatively, in otherembodiments, the active ingredient is in powder form for constitutionwith a suitable vehicle, e.g., sterile pyrogen-free water, before use.

In one aspect, compounds of Formula (I) are prepared as solutions forparenteral injection as described herein or known in the art andadministered with an automatic injector. Automatic injectors, such asthose disclosed in U.S. Pat. Nos. 4,031,893, 5,358,489; 5,540,664;5,665,071, 5,695,472 and WO/2005/087297 (each of which are incorporatedherein by reference for such disclosure) are known. In general, allautomatic injectors contain a volume of solution that includes acompound of Formula (I) to be injected. In general, automatic injectorsinclude a reservoir for holding the solution, which is in fluidcommunication with a needle for delivering the drug, as well as amechanism for automatically deploying the needle, inserting the needleinto the patient and delivering the dose into the patient. Exemplaryinjectors provide about 0.3 mL of solution at about a concentration of0.5 mg to 10 mg of compound of Formula (I) per 1 mL of solution. Eachinjector is capable of delivering only one dose of the compound.

In still other embodiments, the compounds of Formula (I) areadministered topically. The compounds described herein are formulatedinto a variety of topically administrable compositions, such assolutions, suspensions, lotions, gels, pastes, medicated sticks, balms,creams or ointments. Such pharmaceutical compositions optionally containsolubilizers, stabilizers, tonicity enhancing agents, buffers andpreservatives.

In yet other embodiments, the compounds of Formula (I) are formulatedfor transdermal administration. In specific embodiments, transdermalformulations employ transdermal delivery devices and transdermaldelivery patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Invarious embodiments, such patches are constructed for continuous,pulsatile, or on demand delivery of pharmaceutical agents. In additionalembodiments, the transdermal delivery of the compounds of Formula (I) isaccomplished by means of iontophoretic patches and the like. In certainembodiments, transdermal patches provide controlled delivery of thecompounds of Formula (I). In specific embodiments, the rate ofabsorption is slowed by using rate-controlling membranes or by trappingthe compound within a polymer matrix or gel. In alternative embodiments,absorption enhancers are used to increase absorption. Absorptionenhancers or carriers include absorbable pharmaceutically acceptablesolvents that assist passage through the skin. For example, in oneembodiment, transdermal devices are in the form of a bandage comprisinga backing member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundto the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Transdermal formulations described herein may be administered using avariety of devices which have been described in the art. For example,such devices include, but are not limited to, U.S. Pat. Nos. 3,598,122,3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636,3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084,4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303,5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and6,946,144.

The transdermal dosage forms described herein may incorporate certainpharmaceutically acceptable excipients which are conventional in theart. In one embodiment, the transdermal formulations described hereininclude at least three components: (1) a formulation of a compound ofFormula (I); (2) a penetration enhancer; and (3) an aqueous adjuvant. Inaddition, transdermal formulations can include additional componentssuch as, but not limited to, gelling agents, creams and ointment bases,and the like. In some embodiments, the transdermal formulation furtherinclude a woven or non-woven backing material to enhance absorption andprevent the removal of the transdermal formulation from the skin. Inother embodiments, the transdermal formulations described hereinmaintain a saturated or supersaturated state to promote diffusion intothe skin.

In other embodiments, the compounds of Formula (I) are formulated foradministration by inhalation. Various forms suitable for administrationby inhalation include, but are not limited to, aerosols, mists orpowders. Pharmaceutical compositions of Formula (I) are convenientlydelivered in the form of an aerosol spray presentation from pressurizedpacks or a nebuliser, with the use of a suitable propellant (e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas). Inspecific embodiments, the dosage unit of a pressurized aerosol isdetermined by providing a valve to deliver a metered amount. In certainembodiments, capsules and cartridges of, such as, by way of exampleonly, gelatin for use in an inhaler or insufflator are formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

Exemplary intranasal formulations are described in, for example, U.S.Pat. Nos. 4,476,116, 5,116,817 and 6,391,452, each of which isspecifically incorporated by reference. Formulations, which include acompound of Formula (I), which are prepared according to these and othertechniques are prepared as solutions in saline, employing benzyl alcoholor other suitable preservatives, fluorocarbons, and/or othersolubilizing or dispersing agents. See, for example, Ansel, H. C. etal., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed.(1995). Preferably these compositions and formulations are prepared withsuitable nontoxic pharmaceutically acceptable ingredients. Theseingredients are found in sources such as REMINGTON: THE SCIENCE ANDPRACTICE OF PHARMACY, 21st edition, 2005, a standard reference in thefield. The choice of suitable carriers is highly dependent upon theexact nature of the nasal dosage form desired, e.g., solutions,suspensions, ointments, or gels. Nasal dosage forms generally containlarge amounts of water in addition to the active ingredient. Minoramounts of other ingredients such as pH adjusters, emulsifiers ordispersing agents, preservatives, surfactants, gelling agents, orbuffering and other stabilizing and solubilizing agents may also bepresent. Preferably, the nasal dosage form should be isotonic with nasalsecretions.

For administration by inhalation, the compounds described herein, may bein a form as an aerosol, a mist or a powder. Pharmaceutical compositionsdescribed herein are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, such as, by way of example only, gelatin foruse in an inhaler or insufflator may be formulated containing a powdermix of the compound described herein and a suitable powder base such aslactose or starch.

In still other embodiments, the compounds of Formula (I) are formulatedin rectal compositions such as enemas, rectal gels, rectal foams, rectalaerosols, suppositories, jelly suppositories, or retention enemas,containing conventional suppository bases such as cocoa butter or otherglycerides, as well as synthetic polymers such as polyvinylpyrrolidone,PEG, and the like. In suppository forms of the compositions, alow-melting wax such as, but not limited to, a mixture of fatty acidglycerides, optionally in combination with cocoa butter is first melted.

In certain embodiments, pharmaceutical compositions are formulated inany conventional manner using one or more physiologically acceptablecarriers comprising excipients and auxiliaries which facilitateprocessing of the active compounds into preparations which can be usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen. Any pharmaceutically acceptable techniques,carriers, and excipients is optionally used as suitable and asunderstood in the art. Pharmaceutical compositions comprising a compoundof Formula (I) may be manufactured in a conventional manner, such as, byway of example only, by means of conventional mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping or compression processes.

Pharmaceutical compositions include at least one pharmaceuticallyacceptable carrier, diluent or excipient and at least one compound ofFormula (I) described herein as an active ingredient. The activeingredient is in free-acid or free-base form, or in a pharmaceuticallyacceptable salt form. In addition, the methods and pharmaceuticalcompositions described herein include the use of N-oxides, crystallineforms (also known as polymorphs), as well as active metabolites of thesecompounds having the same type of activity. All tautomers of thecompounds described herein are included within the scope of thecompounds presented herein. Additionally, the compounds described hereinencompass unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. The solvatedforms of the compounds presented herein are also considered to bedisclosed herein. In addition, the pharmaceutical compositionsoptionally include other medicinal or pharmaceutical agents, carriers,adjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressure,buffers, and/or other therapeutically valuable substances.

Methods for the preparation of compositions comprising the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically acceptable excipients or carriers to form asolid, semi-solid or liquid. Solid compositions include, but are notlimited to, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include solutions in which acompound is dissolved, emulsions comprising a compound, or a solutioncontaining liposomes, micelles, or nanoparticles comprising a compoundas disclosed herein. Semi-solid compositions include, but are notlimited to, gels, suspensions and creams. The form of the pharmaceuticalcompositions described herein include liquid solutions or suspensions,solid forms suitable for solution or suspension in a liquid prior touse, or as emulsions. These compositions also optionally contain minoramounts of nontoxic, auxiliary substances, such as wetting oremulsifying agents, pH buffering agents, and so forth.

In some embodiments, pharmaceutical composition comprising at least onecompound of Formula (I) illustratively takes the form of a liquid wherethe agents are present in solution, in suspension or both. Typicallywhen the composition is administered as a solution or suspension a firstportion of the agent is present in solution and a second portion of theagent is present in particulate form, in suspension in a liquid matrix.In some embodiments, a liquid composition includes a gel formulation. Inother embodiments, the liquid composition is aqueous.

In certain embodiments, pharmaceutical aqueous suspensions include oneor more polymers as suspending agents. Polymers include water-solublepolymers such as cellulosic polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers such as cross-linkedcarboxyl-containing polymers. Certain pharmaceutical compositionsdescribed herein include a mucoadhesive polymer, selected from, forexample, carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

Pharmaceutical compositions also, optionally include solubilizing agentsto aid in the solubility of a compound of Formula (I). The term“solubilizing agent” generally includes agents that result in formationof a micellar solution or a true solution of the agent. Certainacceptable nonionic surfactants, for example polysorbate 80, are usefulas solubilizing agents, as can ophthalmically acceptable glycols,polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

Furthermore, pharmaceutical compositions optionally include one or morepH adjusting agents or buffering agents, including acids such as acetic,boric, citric, lactic, phosphoric and hydrochloric acids; bases such assodium hydroxide, sodium phosphate, sodium borate, sodium citrate,sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; andbuffers such as citrate/dextrose, sodium bicarbonate and ammoniumchloride. Such acids, bases and buffers are included in an amountrequired to maintain pH of the composition in an acceptable range.

Additionally, pharmaceutical compositions optionally include one or moresalts in an amount required to bring osmolality of the composition intoan acceptable range. Such salts include those having sodium, potassiumor ammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

Other pharmaceutical compositions optionally include one or morepreservatives to inhibit microbial activity. Suitable preservativesinclude mercury-containing substances such as merfen and thiomersal;stabilized chlorine dioxide; and quaternary ammonium compounds such asbenzalkonium chloride, cetyltrimethylammonium bromide andcetylpyridinium chloride.

Still other pharmaceutical compositions include one or more surfactantsto enhance physical stability or for other purposes. Suitable nonionicsurfactants include polyoxyethylene fatty acid glycerides and vegetableoils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40.

Still other pharmaceutical compositions may include one or moreantioxidants to enhance chemical stability where required. Suitableantioxidants include, by way of example only, ascorbic acid and sodiummetabisulfite.

In certain embodiments, pharmaceutical aqueous suspension compositionsare packaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers are used, in which case it istypical to include a preservative in the composition.

In alternative embodiments, other delivery systems for hydrophobicpharmaceutical compounds are employed. Liposomes and emulsions areexamples of delivery vehicles or carriers herein. In certainembodiments, organic solvents such as N-methylpyrrolidone are alsoemployed. In additional embodiments, the compounds described herein aredelivered using a sustained-release system, such as semipermeablematrices of solid hydrophobic polymers containing the therapeutic agent.Various sustained-release materials are useful herein. In someembodiments, sustained-release capsules release the compounds for a fewhours up to over 24 hours. Depending on the chemical nature and thebiological stability of the therapeutic reagent, additional strategiesfor protein stabilization may be employed.

In certain embodiments, the formulations described herein include one ormore antioxidants, metal chelating agents, thiol containing compoundsand/or other general stabilizing agents. Examples of such stabilizingagents, include, but are not limited to: (a) about 0.5% to about 2% w/vglycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% toabout 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e)about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/vpolysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h)arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1)pentosan polysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

Methods of Dosing and Treatment Regimens

In one embodiment, the compound of Formula (I) are used in thepreparation of medicaments for the treatment of PGD₂-dependent orPGD₂-mediated diseases or conditions. In addition, a method for treatingany of the diseases or conditions described herein in a subject in needof such treatment, involves administration of pharmaceuticalcompositions containing at least one compound of Formula (I) or apharmaceutically acceptable salt, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate thereof, in therapeutically effective amounts to said subject.

In certain embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In certain therapeutic applications, the compositions areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest thesymptoms of the disease or condition. Amounts effective for this usedepend on the severity and course of the disease or condition, previoustherapy, the patient's health status, weight, and response to the drugs,and the judgment of the treating physician. Therapeutically effectiveamounts are optionally determined by methods including, but not limitedto, a dose escalation clinical trial.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of the compounds areadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In certain embodiments wherein a patient's status does improve, the doseof drug being administered may be temporarily reduced or temporarilysuspended for a certain length of time (i.e., a “drug holiday”). Inspecific embodiments, the length of the drug holiday is between 2 daysand 1 year, including by way of example only, 2 days, 3 days, 4 days, 5days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days.The dose reduction during a drug holiday is, by way of example only, by10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, in specificembodiments, the dosage or the frequency of administration, or both, isreduced, as a function of the symptoms, to a level at which the improveddisease, disorder or condition is retained. In certain embodiments,however, the patient requires intermittent treatment on a long-termbasis upon any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount variesdepending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but can nevertheless be determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated. In general, however, doses employed for adult humantreatment are typically in the range of 0.02 mg-5000 mg per day,preferably 1-1500 mg per day. In one embodiment, the desired dose isconveniently presented in a single dose or in divided doses administeredsimultaneously (or over a short period of time) or at appropriateintervals, for example as two, three, four or more sub-doses per day.

In some embodiments, compounds of Formula (I) are administeredchronically. In some embodiments, compounds of Formula (I) areadministered intermittently (e.g. drug holiday that includes a period oftime in which the compound is not administered or is administered in areduced amount). In some embodiments, compounds of Formula (I) areadministered in cycles that include: (a) a first period that includesdaily administration of the compound of Formula (I); followed by (b) asecond period that includes a dose reduction of the daily amount of thecompound of Formula (I) that is administered. In some embodiments, thecompound of Formula (I) is not administered in the second period. Insome embodiments, the duration of the first and second periods, as wellas the dose amounts are determined using methods described herein orknown in the art. By way of example only, a drug holiday or a dosereduction period is appropriate depending on the pharmacodynamic profileof the active agent, e.g., the ‘off’ rate of the active agent issignificantly slower than the ‘off’ rate of prostaglandin D₂ from theDP₂ receptor.

In certain embodiments, the pharmaceutical composition described hereinis in unit dosage forms suitable for single administration of precisedosages. In unit dosage form, the formulation is divided into unit dosescontaining appropriate quantities of one or more compound. In specificembodiments, the unit dosage is in the form of a package containingdiscrete quantities of the formulation. Non-limiting examples arepackaged tablets or capsules, and powders in vials or ampoules. Aqueoussuspension compositions are optionally packaged in single-dosenon-re-closeable containers. Alternatively, multiple-dose re-closeablecontainers are used, in which case it is typical to include apreservative in the composition. By way of example only, formulationsfor parenteral injection are, in some embodiments, presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

In one embodiment, the daily dosages appropriate for the compound ofFormula (I) described herein are from about 0.01 to about 10 mg/kg perbody weight. In specific embodiments, an indicated daily dosage in alarge mammal, including, but not limited to, humans, is in the rangefrom about 0.5 mg to about 1000 mg, conveniently administered in divideddoses, including, but not limited to, up to four times a day. In oneembodiment, the daily dosage is administered in extended release form.In certain embodiments, suitable unit dosage forms for oraladministration comprise from about 1 to 500 mg active ingredient. Inother embodiments, the daily dosage or the amount of active in thedosage form are lower or higher than the ranges indicated herein, basedon a number of variables in regard to an individual treatment regime. Invarious embodiments, the daily and unit dosages are altered depending ona number of variables including, but not limited to, the activity of thecompound used, the disease or condition to be treated, the mode ofadministration, the requirements of the individual subject, the severityof the disease or condition being treated, and the judgment of thepractitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens aredetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit is expressed as the ratio between LD₅₀ and ED₅₀. In certainembodiments, the data obtained from cell culture assays and animalstudies are used in formulating the therapeutically effective dailydosage range and/or the therapeutically effective unit dosage amount foruse in mammals, including humans. In some embodiments, the daily dosageamount of the compounds described herein lies within a range ofcirculating concentrations that include the ED₅₀ with minimal toxicity.In certain embodiments, the daily dosage range and/or the unit dosageamount varies within this range depending upon the dosage form employedand the route of administration utilized.

Use of DP₂ Antagonists to Prevent and/or Treat PGD₂-Dependent or PGD₂Mediated Diseases or Conditions

The therapy of PGD₂-dependent or PGD₂-mediated diseases or conditions isdesigned to modulate the activity of DP₂, DP₁ and/or TP. Such modulationincludes, in some embodiments, antagonizing DP₂ activity. In otherembodiments, such modulation includes antagonizing DP₂ and DP₁. Forexample, in one embodiment, a DP₂ antagonist is administered in order todecrease signal transduction initiated by PGD₂ within the individual.

In accordance with one aspect, compositions and methods described hereininclude compositions and methods for treating, preventing, reversing,halting or slowing the progression of PGD₂-dependent or PGD₂ mediateddiseases or conditions once it becomes clinically evident, or treatingthe symptoms associated with or related to PGD₂-dependent or PGD₂mediated diseases or conditions, by administering to the subject acompound of Formula (I) or pharmaceutical composition or medicamentwhich includes a compound of Formula (I). In certain embodiments, thesubject already has a PGD₂-dependent or PGD₂ mediated disease orcondition at the time of administration, or is at risk of developing aPGD₂-dependent or PGD₂ mediated disease or condition.

In certain aspects, the activity of DP₂ in a mammal is directly orindirectly modulated by the administration of (at least once) aneffective amount of at least one compound of Formula (I) orpharmaceutical composition or medicament which includes a compound ofFormula (I) to a mammal. Such modulation includes, but is not limitedto, reducing and/or inhibiting the activity of DP₂. In additionalaspects, the activity of PGD₂ in a mammal is directly or indirectlymodulated, including reducing and/or inhibiting, by the administrationof (at least once) an effective amount of at least one compound ofFormula (I) or pharmaceutical composition or medicament which includes acompound of Formula (I) to a mammal. Such modulation includes, but isnot limited to, reducing and/or inhibiting the activity of DP₂.

In one embodiment, prevention and/or treatment of PGD₂-dependent or PGD₂mediated diseases or conditions comprises administering to a mammal atleast once a therapeutically effective amount of at least one compoundof Formula (I) or pharmaceutical composition or medicament whichincludes a compound of Formula (I). In specific embodiments, thecompound administered to the mammal is a compound of Formula (I). Insome embodiments, there is provided a method of treating PGD₂-dependentor PGD₂ mediated diseases or conditions that include, but are notlimited to, bone diseases and disorders, cardiovascular diseases anddisorders, inflammatory diseases and disorders, immunological diseasesor disorders, dermatological diseases and disorders, ocular diseases anddisorders, cancer and other proliferative diseases and disorders,respiratory diseases and disorder, and non-cancerous disorders.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for treating respiratory diseasescomprising administering to the mammal at least once an effective amountof at least one compound of Formula (I) or pharmaceutical composition ormedicament which includes a compound of Formula (I). By way of example,in some embodiments, the respiratory disease is asthma. Otherrespiratory diseases include, but are not limited to, adult respiratorydistress syndrome and allergic (extrinsic) asthma, non-allergic(intrinsic) asthma, acute severe asthma, chronic asthma, clinicalasthma, neutrophilic asthma, nocturnal asthma, allergen-induced asthma,aspirin-sensitive asthma, exercise-induced asthma, isocapnichyperventilation, child-onset asthma, adult-onset asthma, cough-variantasthma, occupational asthma, steroid-resistant asthma, seasonal asthma,allergic rhinitis, vascular responses, endotoxin shock, fibrogenesis,pulmonary fibrosis, allergic diseases, chronic inflammation, and adultrespiratory distress syndrome.

By way of example only, included in such treatment methods are methodsfor preventing chronic obstructive pulmonary disease comprisingadministering to the mammal at least once an effective amount of atleast one compound of Formula (I) or pharmaceutical composition ormedicament which includes a compound of Formula (I). In addition,chronic obstructive pulmonary disease includes, but is not limited to,chronic bronchitis or emphysema, pulmonary hypertension, interstitiallung fibrosis and/or airway inflammation and cystic fibrosis.

By way of example only, included in such treatment methods are methodsfor preventing increased mucosal secretion and/or edema in a disease orcondition comprising administering to the mammal at least once aneffective amount of at least one compound of Formula (I) orpharmaceutical composition or medicament which includes a compound ofFormula (I).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing or treatingvasoconstriction, atherosclerosis and its sequelae myocardial ischemia,myocardial infarction, aortic aneurysm, vasculitis and stroke comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (I) or pharmaceutical composition ormedicament which includes a compound of Formula (I).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for reducing cardiac reperfusion injuryfollowing myocardial ischemia and/or endotoxic shock comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (I) or pharmaceutical composition ormedicament which includes a compound of Formula (I).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for reducing the constriction of bloodvessels in a mammal comprising administering at least once to the mammalan effective amount of at least one compound of Formula (I) orpharmaceutical composition or medicament which includes a compound ofFormula (I).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for lowering or preventing an increase inblood pressure of a mammal comprising administering at least once to themammal an effective amount of at least one compound of Formula (I) orpharmaceutical composition or medicament which includes a compound ofFormula (I).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing or treating eosinophiland/or basophil and/or dendritic cell and/or neutrophil and/or monocyteand/or T-cell recruitment comprising administering at least once to themammal an effective amount of at least one compound of Formula (I) orpharmaceutical composition or medicament which includes a compound ofFormula (I).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the prevention or treatment of abnormalbone remodeling, loss or gain, including diseases or conditions as, byway of example, osteopenia, osteoporosis, Paget's disease, cancer andother diseases comprising administering at least once to the mammal aneffective amount of at least one compound of Formula (I) orpharmaceutical composition or medicament which includes a compound ofFormula (I).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing ocular inflammation andallergic conjunctivitis, vernal keratoconjunctivitis, and papillaryconjunctivitis comprising administering at least once to the mammal aneffective amount of at least one compound of Formula (I) orpharmaceutical composition or medicament which includes a compound ofFormula (I).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing otitis, otitis mediacomprising administering at least once to the mammal an effective amountof at least one compound of Formula (I) or pharmaceutical composition ormedicament which includes a compound of Formula (I).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing CNS disorders comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (I) or pharmaceutical composition ormedicament which includes a compound of Formula (I). CNS disordersinclude, but are not limited to, multiple sclerosis, Parkinson'sdisease, Alzheimer's disease, stroke, cerebral ischemia, retinalischemia, post-surgical cognitive dysfunction, migraine, pain,peripheral neuropathy/neuropathic pain, spinal cord injury, cerebraledema and head injury.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the treatment of cancer comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (I), or pharmaceutical composition ormedicament which includes a compound of Formula (I). The type of cancermay include, but is not limited to, pancreatic cancer and other solid orhematological tumors.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing or reducing the chances ofendotoxic shock and septic shock comprising administering at least onceto the mammal an effective amount of at least one compound of Formula(I) or pharmaceutical composition or medicament which includes acompound of Formula (I).

By way of example only, included in the prevention/treatment methodsdescribed herein methods for preventing, treating or alleviatingrheumatoid arthritis and osteoarthritis comprising administering atleast once to the mammal an effective amount of at least one compound ofFormula (I) or pharmaceutical composition or medicament which includes acompound of Formula (I).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing increased, reducing theincidences of or treating gastrointestinal diseases comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (I) or pharmaceutical composition ormedicament which includes a compound of Formula (I). Suchgastrointestinal diseases include, by way of example only, inflammatorybowel disease (IBD), colitis and Crohn's disease.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the reduction or treatment ofinflammation and/or preventing, reducing the incidences of or treatingacute or chronic transplant rejection (including any vascularabnormality associated with acute or chronic rejection) or preventing ortreating tumors or accelerating the healing of wounds comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (I) or pharmaceutical composition ormedicament which includes a compound of Formula (I).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the prevention or treatment ofrejection or dysfunction in a transplanted organ or tissue comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (I) or pharmaceutical composition ormedicament which includes a compound of Formula (I).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for treating inflammatory responses of theskin comprising administering at least once to the mammal an effectiveamount of at least one compound of Formula (I) or pharmaceuticalcomposition or medicament which includes a compound of Formula (I). Suchinflammatory responses of the skin include, by way of example,psoriasis, dermatitis, contact dermatitis, eczema, urticaria, rosacea,wound healing and scarring. In another aspect are methods for reducingpsoriatic lesions in the skin, joints, or other tissues or organs,comprising administering at least once to the mammal an effective amountof at least one compound of Formula (I) or pharmaceutical composition ormedicament which includes a compound of Formula (I).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the treatment of cystitis, including,e.g., interstitial cystitis, comprising administering at least once tothe mammal an effective amount of at least one compound of Formula (I)or pharmaceutical composition or medicament which includes a compound ofFormula (I).

In one aspect, the compound of Formula (I) is used in the treatment ofasthma, rhinitis, allergic conjuctivitis, atopic dermatitis, chronicobstructive pulmonary disease (COPD), pulmonary hypertension,interstitial lung fibrosis, arthritis, allergy, psoriasis, inflammatorybowel disease, adult respiratory distress syndrome, myocardialinfarction, aneurysm, stroke, cancer, wound healing, endotoxic shock,pain, inflammatory conditions, eosinophilic esophagitis,eosinophil-associated gastrointestinal disorders (EGID), idiopathichypereosinophilic syndrome, otitis, airway constriction, mucussecretion, nasal congestion, increased microvascular permeability andrecruitment of eosinophils, urticaria, sinusitis, angioedema,anaphylaxia, chronic cough or Churg Strauss syndrome.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the treatment of Familial MediterraneanFever comprising administering at least once to the mammal an effectiveamount of at least one compound of Formula (I) or pharmaceuticalcomposition or medicament which includes a compound of Formula (I).

In one aspect, compounds of Formula (I) are used in the treatment ofPGD₂-dependent or PGD₂-mediated diseases, disorders or conditions asdisclosed herein. In one aspect, compounds of Formula (I) are DP₂antagonists. In one aspect, the compounds of Formula (I) exhibitnegligible modulatory activty on CETP and/or PPAR receptors. CETP assaysare known (Epps et al. Chem. Phys. Lipids. 77, 51-63, 1995). PPAR assaysare known (Example 48 of US 2006/0058301).

Combination Treatments

In certain instances, it is appropriate to administer at least onecompound of Formula (I) in combination with another therapeutic agent.By way of example only, if one of the side effects experienced by apatient upon receiving one of the compounds herein is inflammation, thenit may be appropriate to administer an anti-inflammatory agent incombination with the initial therapeutic agent. Or, in one embodiment,the therapeutic effectiveness of one of the compounds described hereinis enhanced by administration of an adjuvant (i.e., by itself theadjuvant may have minimal therapeutic benefit, but in combination withanother therapeutic agent, the overall therapeutic benefit to thepatient is enhanced). Or, in some embodiments, the benefit ofexperienced by a patient is increased by administering one of thecompounds described herein with another therapeutic agent (which alsoincludes a therapeutic regimen) that also has therapeutic benefit. Inone specific embodiment, the therapeutic benefit of treating asthma byadministering at least one of the compounds described herein isincreased by also providing the patient with other therapeutic agents ortherapies for asthma. In any case, regardless of the disease, disorderor condition being treated, the overall benefit experienced by thepatient may simply be additive of the two therapeutic agents or thepatient may experience a synergistic benefit.

In certain embodiments, different therapeutically-effective dosages ofthe compounds disclosed herein will be utilized in formulatingpharmaceutical composition and/or in treatment regimens when thecompounds disclosed herein are administered in combination with one ormore additional agent, such as an additional therapeutically effectivedrug, an adjuvant or the like. Therapeutically-effective dosages ofdrugs and other agents for use in combination treatment regimens can bedetermined by means similar to those set forth hereinabove for theactives themselves. Furthermore, the methods of prevention/treatmentdescribed herein encompasses the use of metronomic dosing, i.e.,providing more frequent, lower doses in order to minimize toxic sideeffects. In some embodiments, a combination treatment regimenencompasses treatment regimens in which administration of a DP₂antagonist described herein is initiated prior to, during, or aftertreatment with a second agent described above, and continues until anytime during treatment with the second agent or after termination oftreatment with the second agent. It also includes treatments in which aDP₂ antagonist described herein and the second agent being used incombination are administered simultaneously or at different times and/orat decreasing or increasing intervals during the treatment period.Combination treatment further includes periodic treatments that startand stop at various times to assist with the clinical management of thepatient. For example, in one embodiment, a DP₂ antagonist describedherein in the combination treatment is administered weekly at the onsetof treatment, decreasing to biweekly, and decreasing further asappropriate.

Compositions and methods for combination therapy are provided herein. Inaccordance with one aspect, the pharmaceutical compositions disclosedherein are used to treat PGD₂-dependent or PGD₂ mediated conditions. Inaccordance with another aspect, the pharmaceutical compositionsdisclosed herein are used to treat respiratory diseases (e.g., asthma),where treatment with a DP₂ antagonist is indicated and to inducebronchodilation in a subject. In one embodiment, the pharmaceuticalcompositions disclosed herein are used to treat airways or nasalinflammation diseases such as asthma and rhinitis.

In one embodiment, pharmaceutical compositions disclosed herein are usedto treat a subject suffering from a vascular inflammation-drivendisorder. In one embodiment, the pharmaceutical compositions disclosedherein are used to treat skin inflammation diseases such as atopicdermatitis.

In certain embodiments, combination therapies described herein are usedas part of a specific treatment regimen intended to provide a beneficialeffect from the co-action of a DP₂ described herein and a concurrenttreatment. It is understood that the dosage regimen to treat, prevent,or ameliorate the condition(s) for which relief is sought, is modifiedin accordance with a variety of factors. These factors include the typeof respiratory disorder and the type of bronchoconstriction orinflammation from which the subject suffers, as well as the age, weight,sex, diet, and medical condition of the subject. Thus, in someinstances, the dosage regimen actually employed varies and, in someembodiments, deviates from the dosage regimens set forth herein.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated and so forth. In additional embodiments, whenco-administered with one or more biologically active agents, thecompound provided herein is administered either simultaneously with thebiologically active agent(s), or sequentially. If administeredsequentially, the attending physician decides on the appropriatesequence of administering protein in combination with the biologicallyactive agent(s).

In combination therapies, the multiple therapeutic agents (one of whichis one of the compounds described herein) are administered in any orderor even simultaneously. If administration is simultaneous, the multipletherapeutic agents are, by way of example only, provided in a single,unified form, or in multiple forms (e.g., as a single pill or as twoseparate pills). In one embodiment, one of the therapeutic agents isgiven in multiple doses, and in another, two (or more if present) aregiven as multiple doses. In some embodiments of non-simultaneousadministration, the timing between the multiple doses vary from morethan zero weeks to less than four weeks. In addition, the combinationmethods, compositions and formulations are not to be limited to the useof only two agents; the use of multiple therapeutic combinations is alsoenvisioned.

In additional embodiments, the compounds of Formula (I) are used incombination with procedures that provide additional or synergisticbenefit to the patient. By way of example only, patients are expected tofind therapeutic and/or prophylactic benefit in the methods describedherein, wherein pharmaceutical composition of Formula (I) and/orcombinations with other therapeutics are combined with genetic testingto determine whether that individual is a carrier of a mutant gene thatis known to be correlated with certain diseases or conditions.

The compounds of Formula (I) and combination therapies are administeredbefore, during or after the occurrence of a disease or condition, andthe timing of administering the composition containing a compoundvaries. Thus, in one embodiment, the compounds described herein are usedas a prophylactic and are administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. In another embodiment, thecompounds and compositions are administered to a subject during or assoon as possible after the onset of the symptoms. The administration ofthe compounds are initiated within the first 48 hours of the onset ofthe symptoms, preferably within the first 48 hours of the onset of thesymptoms, more preferably within the first 6 hours of the onset of thesymptoms, and most preferably within 3 hours of the onset of thesymptoms. The initial administration is accomplished via any practicalroute, such as, for example, by intravenous injection, a bolusinjection, infusion over 5 minutes to about 5 hours, a pill, a capsule,transdermal patch, buccal delivery, and the like, or combinationthereof. In specific embodiments, a compound described herein isadministered as soon as is practicable after the onset of a disease orcondition is detected or suspected, and for a length of time necessaryfor the treatment of the disease, such as, for example, from about 1month to about 3 months. In some embodiments, the length required foreffective treatment varies, and the treatment length is adjusted to suitthe specific needs of each subject. For example, in specificembodiments, a compound described herein or a formulation containing thecompound is administered for at least 2 weeks, about 1 month to about 5years, or from about 1 month to about 3 years.

By way of example, therapies which combine compounds of Formula (I) withinhibitors of PGD₂ synthesis or PGD₂ receptor antagonists, either actingat the same or other points in the PGD₂ synthesis pathway, areencompassed herein for treating PGD₂-dependent or PGD₂ mediated diseasesor conditions. In addition, by way of example, encompassed herein aretherapies that combine compounds of Formula (I) with inhibitors ofinflammation for treating PGD₂-dependent or PGD₂ mediated diseases orconditions.

Anti-Inflammatory Agents

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases includeadministration to a patient compounds, pharmaceutical compositions, ormedicaments described herein in combination with an anti-inflammatoryagent including, but not limited to, non-steroidal anti-inflammatorydrugs (NSAIDs) and corticosteroids (glucocorticoids). Anti-inflammatoryagents include, but are not limited to: arthrotec, mesalamine,auralglan, sulfasalazine, daypro, etodolac, ponstan, and solumedrol;non-steroidal anti-inflammatory agents; corticosteroids; and leukotrienepathway modulators (e.g. montelukast, zilueton).

By way of example only, asthma is a chronic inflammatory diseasecharacterized by pulmonary eosinophilia and airway hyperresponsiveness.In patients with asthma, PGD₂ is released from mast cells, eosinophils,and basophils. PGD₂ is involved in contraction of airway smooth muscle,an increase in vascular permeability and mucus secretions, and has beenreported to attract and activate inflammatory cells in the airways ofasthmatics. Thus, in another embodiment described herein, the methodsfor treatment of respiratory diseases include administration to apatient compounds, pharmaceutical compositions, or medicaments describedherein in combination with an anti-inflammatory agent.

NSAIDs include, but are not limited to: aspirin, salicylic acid,gentisic acid, choline magnesium salicylate, choline salicylate, cholinemagnesium salicylate, choline salicylate, magnesium salicylate, sodiumsalicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium,fluorobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolactromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin,sulindac, tolmetin, meclofenamate, meclofenamate sodium, mefenamic acid,piroxicam, meloxicam, COX-2 specific inhibitors (such as, but notlimited to, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib,lumiracoxib, CS-502, JTE-522, L-745,337 and NS398).

Corticosteroids, include, but are not limited to: betamethasone(Celestone), prednisone (Deltasone), alclometasone, aldosterone,amcinonide, beclometasone, betamethasone, budesonide, ciclesonide,clobetasol, clobetasone, clocortolone, cloprednol, cortisone,cortivazol, deflazacort, deoxycorticosterone, desonide, desoximetasone,desoxycortone, dexamethasone, diflorasone, diflucortolone,difluprednate, fluclorolone, fludrocortisone, fludroxycortide,flumetasone, flunisolide, fluocinolone acetonide, fluocinonide,fluocortin, fluocortolone, fluorometholone, fluperolone, fluprednidene,fluticasone, formocortal, halcinonide, halometasone,hydrocortisone/cortisol, hydrocortisone aceponate, hydrocortisonebuteprate, hydrocortisone butyrate, loteprednol, medrysone,meprednisone, methylprednisolone, methylprednisolone aceponate,mometasone furoate, paramethasone, prednicarbate,prednisone/prednisolone, rimexolone, tixocortol, triamcinolone, andulobetasol.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases includeadministration to a patient compounds, pharmaceutical compositions, ormedicaments described herein in combination in combination with NSAIDsand NO-donors or NSAIDs and proton-pump inhibitors.

PGD₂ Receptor Antagonists

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases includesadministering to a patient compounds, pharmaceutical compositions, ormedicaments described herein in combination with other PGD₂ receptorantagonists including, but are not limited to, DP₁ receptor antagonistsand TP receptor antagonists. In another embodiment described herein,methods for treatment of PGD₂-dependent or PGD₂ mediated conditions ordiseases includes administered to a patient compounds, pharmaceuticalcompositions, or medicaments described herein in combination with a DP₁receptor antagonist. DP₁ receptor antagonists include, but are notlimited to, BWA868C (Sharif et al., Br. J. Pharmacol., 2000 November;131(6):1025-38), MK-0524 (Sturino et al, J. Med. Chem., 2007, 50,794-806 and Cheng et al, PNAS, 2006 Apr. 25; 103(17):6682-7.) and S-5751(Arimura et al., J. Pharmacol. Exp. Ther., 2001 August; 298(2):411-9).For some patients, the most appropriate formulation or method of use ofsuch combination treatments depends on the type of PGD₂-dependent orPGD₂ mediated disorder, the time period in which the DP₂ antagonist actsto treat the disorder and/or the time period in which the DP₁ receptorantagonist acts to prevent DP₁ receptor activity. By way of exampleonly, some embodiments described herein provide for such combinationtreatments that are used for treating a patient suffering fromrespiratory disorders such as asthma and rhinitis.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases includesadministering to a patient compounds, pharmaceutical compositions, ormedicaments described herein in combination with a TP receptorantagonist. TP receptor antagonists include, but are not limited to,Ramatroban (“Bayer™”), GR32191 (Beasley et al., J. Appl. Physiol., 1989April; 66(4):1685-93), ICI192605 (Boersma et al., Br. J. Pharmacol.,1999 December; 128(7):1505-12) and derivatives or analogs thereof. Suchcombinations may be used to treat PGD₂-dependent or PGD₂ mediateddisorders, including respiratory disorders.

In one embodiment, the co-administration of a DP₂ receptor antagonistwith a DPI receptor antagonist or a TP receptor antagonist hastherapeutic benefit over and above the benefit derived from theadministration of a either a DP₂ antagonist, DP₁ antagonist or a TPantagonist alone. In the case that substantial inhibition of PGD₂activity has undesired effects, partial inhibition of this pathwaythrough the amelioration of the effects of the proinflammatory agonistscombined with the block of the DP₁ receptor, TP receptor and/or DP₂receptor may afford substantial therapeutic benefits, particularly forrespiratory diseases.

Other Combination Therapies

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such asproliferative disorders, including cancer, comprises administration to apatient compounds, pharmaceutical compositions, or medicaments describedherein in combination with at least one additional agent selected, byway of example only, alemtuzumab, arsenic trioxide, asparaginase(pegylated or non-), bevacizumab, cetuximab, platinum-based compoundssuch as cisplatin, cladribine, daunorubicin/doxorubicin/idarubicin,irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate,Paclitaxel™, taxol, temozolomide, thioguanine, or classes of drugsincluding hormones (an antiestrogen, an antiandrogen, or gonadotropinreleasing hormone analogues, interferons such as alpha interferon,nitrogen mustards such as busulfan or melphalan or mechlorethamine,retinoids such as tretinoin, topoisomerase inhibitors such as irinotecanor topotecan, tyrosine kinase inhibitors such as gefinitinib orimatinib, or agents to treat signs or symptoms induced by such therapyincluding allopurinol, filgrastim, granisetron/ondansetron/palonosetron,dronabinol.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of transplanted organs or tissues or cells, comprisesadministration to a patient compounds, pharmaceutical compositions, ormedicaments described herein in combination with at least one additionalagent selected from, by way of example only, azathioprine, acorticosteroid, cyclophosphamide, cyclosporin, dacluzimab, mycophenolatemofetil, OKT3, rapamycin, tacrolimus, thymoglobulin.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such asatherosclerosis, comprises administration to a patient compounds,pharmaceutical compositions, or medicaments described herein incombination with at least one additional agent selected, by way ofexample only, HMG-CoA reductase inhibitors (e.g., statins in theirlactonized or dihydroxy open acid forms and pharmaceutically acceptablesalts and esters thereof, including but not limited to lovastatin;simvastatin; dihydroxy open-acid simvastatin, particularly the ammoniumor calcium salts thereof; pravastatin, particularly the sodium saltthereof; fluvastatin, particularly the sodium salt thereof;atorvastatin, particularly the calcium salt thereof; nisvastatin, alsoreferred to as NK-104; rosuvastatin); agents that have bothlipid-altering effects and other pharmaceutical activities; HMG-CoAsynthase inhibitors; cholesterol absorption inhibitors such asezetimibe; cholesterol ester transfer protein (CETP) inhibitors, forexample JTT-705 and CP529, 414; squalene epoxidase inhibitors; squalenesynthetase inhibitors (also known as squalene synthase inhibitors);acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors includingselective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors ofACAT-1 and -2; microsomal triglyceride transfer protein (MTP)inhibitors; probucol; niacin; bile acid sequestrants; LDL (low densitylipoprotein) receptor inducers; platelet aggregation inhibitors, forexample glycoprotein IIb/IIIa fibrinogen receptor antagonists andaspirin; human peroxisome proliferator activated receptor gamma (PPARγ)agonists, including the compounds commonly referred to as glitazones,for example troglitazone, pioglitazone and rosiglitazone and includingthose compounds included within the structural class known asthiazolidinediones as well as those PPARγ agonists outside thethiazolidinedione structural class; PPARα agonists such as clofibrate,fenofibrate including micronized fenofibrate, and gemfibrozil; PPAR dualα/γ agonists such as5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide,known as KRP-297; vitamin B6 (also known as pyridoxine) and thepharmaceutically acceptable salts thereof such as the HCl salt; vitaminB12 (also known as cyanocobalamin); folic acid or a pharmaceuticallyacceptable salt or ester thereof such as the sodium salt and themethylglucamine salt; anti-oxidant vitamins such as vitamin C and E andbeta carotene; beta-blockers; angiotensin II antagonists such aslosartan; angiotensin converting enzyme inhibitors such as enalapril andcaptopril; calcium channel blockers such as nifedipine and diltiazam;endothelian antagonists; agents that enhance ABC 1 gene expression; FXRand LXR ligands including both inhibitors and agonists; bisphosphonatecompounds such as alendronate sodium; and cyclooxygenase-2 inhibitorssuch as rofecoxib and celecoxib.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of stroke, comprises administration to a patient compounds,pharmaceutical compositions, or medicaments described herein incombination with at least one additional agent selected from, by way ofexample only, COX-2 inhibitors; nitric oxide synthase inhibitors, suchas N-(3-(aminomethyl)benzyl)acetamidine; Rho kinase inhibitors, such asfasudil; angiotension II type-1 receptor antagonists, includingcandesartan, losartan, irbesartan, eprosartan, telmisartan andvalsartan; glycogen synthase kinase 3 inhibitors; sodium or calciumchannel blockers, including crobenetine; p38 MAP kinase inhibitors,including SKB 239063; thromboxane AX-synthetase inhibitors, includingisbogrel, ozagrel, ridogrel and dazoxiben; statins (HMG CoA reductaseinhibitors), including lovastatin, simvastatin, dihydroxy open-acidsimvastatin, pravastatin, fluvastatin, atorvastatin, nisvastatin, androsuvastatin; neuroprotectants, including free radical scavengers,calcium channel blockers, excitatory amino acid antagonists, growthfactors, antioxidants, such as edaravone, vitamin C, TROLOX™, citicolineand minicycline, and reactive astrocyte inhibitors, such as(2R)-2-propyloctanoic acid; beta andrenergic blockers, such aspropranolol, nadolol, timolol, pindolol, labetalol, metoprolol,atenolol, esmolol and acebutolol; NMDA receptor antagonists, includingmemantine; NR2B antagonists, such as traxoprodil; 5-HT1A agonists;receptor platelet fibrinogen receptor antagonists, including tirofibanand lamifiban; thrombin inhibitors; antithrombotics, such as argatroban;antihypertensive agents, such as enalapril; vasodilators, such ascyclandelate; nociceptin antagonists; DPIV antagonists; CETP inhibitors;GABA 5 inverse agonists; and selective androgen receptor modulators.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of pulmonary fibrosis, comprises administration to a patientcompounds, pharmaceutical compositions, or medicaments described hereinin combination with at least one additional agent selected from, by wayof example only, anti-inflammatory agents, such as corticosteroids,azathioprine or cyclophosphamide.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of interstitial cystitis, comprises administration to a patientcompounds, pharmaceutical compositions, or medicaments described hereinin combination with at least one additional agent selected from, by wayof example only, dimethylsulfoxide, omalizumab, and pentosanpolysulfate.

In another embodiment described herein, methods for treatment ofPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of disorders of bone, comprises administration to a patientcompounds, pharmaceutical compositions, or medicaments described hereinin combination with at least one additional agent selected from the, byway of example only, minerals, vitamins, bisphosphonates, anabolicsteroids, parathyroid hormone or analogs, and cathepsin K inhibitors.

In yet another embodiment described herein, methods for treatingPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of respiratory disorders (e.g., asthma, COPD and rhinitis),comprises administration to a patient compounds, pharmaceuticalcompositions, or medicaments described herein in combination with atleast one respiratory agent. Respiratory agents include, but are notlimited to, bronchodilators (e.g., sympathomimetic agents and xanthinederivatives), leukotriene receptor antagonists, leukotriene formationinhibitors, leukotriene modulators, nasal decongestants, respiratoryenzymes, lung surfactants, antihistamines (e.g., Mepyramine(pyrilamine), Antazoline, Diphenhydramine, Carbinoxamine, Doxylamine,Clemastine, Dimenhydrinate, Pheniramine, Chlorphenamine(chlorpheniramine), Dexchlorpheniramine, Brompheniramine, Triprolidine,cetirizine, Cyclizine, Chlorcyclizine, Hydroxyzine, Meclizine,loratadine, desloratidine, Promethazine, Alimemazine (trimeprazine),Cyproheptadine, Azatadine, Ketotifen, Acrivastine, Astemizole,Cetirizine, Mizolastine, Terfenadine, Azelastine, Levocabastine,Olopatadine, Levocetirizine, Fexofenadine), mucolytics, corticosteroids,glucocorticoids, anticholinergics, antitussives, analgesics,expectorants, albuterol, ephedrine, epinephrine, fomoterol,metaproterenol, terbutaline, budesonide, ciclesonide, dexamethasone,flunisolide, fluticasone propionate, triamcinolone acetonide,ipratropium bromide, pseudoephedrine, theophylline, montelukast,zafirlukast, pranlukast, tomelukast, ambrisentan, bosentan, enrasentan,sitaxsentan, tezosentan, iloprost, treprostinil, pirfenidone, FLAPinhibitors, FLAP modulators, 5-LO inhibitors, BLT1 receptor antagonistsand BLT2 receptor antagonists.

In a specific embodiment described herein, methods for treatingPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of asthma and/or COPD, comprises administration to a patientanti-inflammatory agents. In certain embodiments, methods for treatingPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of asthma and/or COPD, comprise administration to a patientcompounds, pharmaceutical compositions, or medicaments described hereinin combination with at least one additional agent selected from, but notlimited to, epinephrine, isoproterenol, orciprenaline, bronchodilators,glucocorticoids, leukotriene modifiers, mast-cell stabilizers,xanthines, anticholinergics, β-2 agonists, FLAP inhibitors, FLAPmodulators or 5-LO inhibitors. β-2 agonists include, but are not limitedto, short-acting β-2 agonists (e.g., salbutamol (albuterol),levalbuterol, terbutaline, pirbuterol, procaterol, metaproterenol,fenoterol and bitolterol mesylate) and long-acting β-2 agonists (e.g.,salmeterol, formoterol, bambuterol and clenbuterol). FLAP inhibitorsand/or FLAP modulators include, but are not limited to,3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionicacid,3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionicacid, MK-886, MK-0591, DG-031 (BAY-X1005) and compounds found in US2007/0225285, US 2007/0219206, US 2007/0173508, US 2007/0123522 and US2007/0105866 (each of which are hereby incorporated by reference).Glucocorticoids include, but are not limited to, beclometasone,budesonide, ciclesonide, fluticasone and mometasone. Anticholinergicsinclude, but are not limited to, ipratropium and tiotropium. Mast cellstabilizers include, but are not limited to, cromoglicate andnedocromil. Xanthines include, but are not limited to, amminophylline,theobromine and theophylline. Leukotriene antagonists include, but arenot limited to, montelukast, tomelukast, pranlukast and zafirlukast.5-LO inhibitors include, but are not limited to, zileuton, VIA-2291(ABT761), MK-0633, CJ-13,610 (PF-4191834), AZ-4407 and ZD-2138 andcompounds found in US 2007/0149579, WO2007/016784.

In another specific embodiment described herein, methods for treatingPGD₂-dependent or PGD₂ mediated conditions or diseases, such as thetherapy of rhinitis, comprises administration to a patient compounds,pharmaceutical compositions, or medicaments described herein incombination with at least one additional agent selected from, by way ofexample only, antihistamines, leukotriene antagonists, corticosteroidsand decongestants. Leukotriene antagonists include, but are not limitedto, montelukast, tomelukast, pranlukast and zafirlukast.

In another aspect, methods for treating PGD₂-dependent or PGD₂ mediatedconditions or diseases, include administering a DP₂ antagonist describedherein in combination with other agents to treat respiratory diseases orconditions. Therapeutic agents used in the treatment of respiratoryconditions and disorders, such as, but not limited to asthma, include:glucocorticoids, such as, ciclesonide, beclomethasone, budesonide,flunisolide, fluticasone, mometasone, and triamcinolone; leukotrienemodifiers, such as, montelukast, zafirlukast, pranlukast, and zileuton;mast cell stabilizers, such as, cromoglicate (cromolyn), and nedocromil;antimuscarinics/anticholinergics, such as, ipratropium, oxitropium, andtiotropium; methylxanthines, such as, theophylline and aminophylline;antihistamine, such as, mepyramine (pyrilamine), antazoline,diphenhydramine, carbinoxamine, doxylamine, clemastine, dimenhydrinate,pheniramine, chlorphenamine (chlorpheniramine), dexchlorphenamine,brompheniramine, triprolidine, cyclizine, chlorcyclizine, hydroxyzine,meclizine, promethazine, alimemazine (trimeprazine), cyproheptadine,azatadine, ketotifen, acrivastine, astemizole, cetirizine, loratadine,mizolastine, terfenadine, fexofenadine, levocetirizine, desloratadine,fexofenadine; omalizumab, an IgE blocker; beta2-adrenergic receptoragonists, such as: short acting beta2-adrenergic receptor agonists, suchas, salbutamol (albuterol), levalbuterol, terbutaline, pirbuterol,procaterol, metaproterenol, fenoterol, bitolterol mesylate; andlong-acting beta2-adrenergic receptor agonists, such as, salmeterol,formoterol, bambuterol.

In one aspect, DP₂ anatogonists described herein are admistered incombination with one or more agents used to treat used to treat asthma,including, but not limited to: combination inhalers (fluticasone andsalmeterol oral inhalation (e.g. Advair)); inhaled Beta-2 agonists(albuterol inhaler; albuterol nebulizer solution; formoterol;isoproterenol oral inhalation; levalbuterol; metaproterenol inhalation;pirbuterol acetate oral inhalation; salmeterol aerosol inhalation;salmeterol powder inhalation; terbutaline inhaler); inhaledcorticosteroids (beclomethasone oral inhalation; budesonide inhalationsolution; budesonide inhaler; flunisolide oral inhalation; fluticasoneinhalation aerosol; fluticasone powder for oral inhalation; mometasoneinhalation powder; triamcinolone oral inhalation); leukotriene modifiers(montelukast; zafirlukast; pranlukast; tomelukast; zileuton); mast cellstabilizers (cromolyn inhaler; nedocromil oral inhalation); monoclonalantibodies (omalizumab); oral Beta-2 agonists (albuterol oral syrup;albuterol oral tablets; metaproterenol; terbutaline); bronchodilator(aminophylline; oxtriphylline; theophylline).

In one aspect, DP₂ anatogonists described herein are admistered incombination with one or more agents used to treat allergy, including,but not limited to: antihistamine and decongestant combinations(cetirizine and pseudoephedrine; desloratadine and pseudoephedrine ER;fexofenadine and pseudoephedrine; loratadine and pseudoephedrine);antihistamines (azelastine nasal spray; brompheniramine; brompheniramineoral suspension; carbinoxamine; cetirizine; chlorpheniramine;clemastine; desloratadine; dexchlorpheniramine ER; dexchlorpheniramineoral syrup; diphenhydramine oral; fexofenadine; loratadine;promethazine); decongestants (pseudoephedrine); leukotriene modifiers(montelukast; montelukast granules); nasal anticholinergics(ipratropium); nasal corticosteroids (beclomethasone nasal inhalation;budesonide nasal inhaler; flunisolide nasal inhalation; fluticasonenasal inhalation; mometasone nasal spray; triamcinolone nasalinhalation; triamcinolone nasal spray); nasal decongestants(phenylephrine); nasal mast cell stabilizers (cromolyn nasal spray).

In one aspect, DP₂ anatogonists described herein are admistered incombination with one or more agents used to treat chronic obstructivepulmonary disease (COPD), including, but not limited to:anticholinergics—ipratropium bromide oral inhalation); combinationInhalers (albuterol and ipratropium (e.g. Combivent, DuoNeb);fluticasone and salmeterol oral inhalation (e.g. Advair));corticosteroids (dexamethasone tablets; fludrocortisone acetate;hydrocortisone tablets; methylprednisolone; prednisolone liquid;prednisone oral; triamcinolone oral); inhaled Beta-2 Agonists (albuterolinhaler; albuterol nebulizer solution; formoterol; isoproterenol oralinhalation; levalbuterol; metaproterenol inhalation; pirbuterol acetateoral inhalation; salmeterol aerosol inhalation; salmeterol powderinhalation; terbutaline inhaler); inhaled Corticosteroids(beclomethasone oral inhalation; budesonide inhalation solution;budesonide inhaler; flunisolide oral inhalation; fluticasone inhalationaerosol; fluticasone powder for oral inhalation; triamcinolone oralinhalation); mukolytics (guaifenesin); oral Beta-2 agonists (albuteroloral syrup; albuterol oral tablets; metaproterenol; terbutaline);bronchodilator (aminophylline; oxtriphylline; theophylline).

In one embodiment, DP₂ anatogonists described herein are administered toa patient in combination with inhaled corticosteroids.

In one embodiment, DP₂ anatogonists described herein are administered toa patient in combination with beta2-adrenergic receptor agonists. In oneembodiment, DP₂ anatogonists described herein are administered to apatient in combination with short acting beta2-adrenergic receptoragonists. In one embodiment, DP₂ anatogonists described herein areadministered to a patient in combination with long-actingbeta2-adrenergic receptor agonists.

As discussed herein, the administration of compounds of Formula (I) isdesigned to anatagonize the activity of DP₂. For example, in specificembodiments, the administration of a DP₂ inhibitor decreases signaltransduction initiated by PGD₂ within the individual.

Thus, in accordance with one aspect, methods described herein includethe diagnosis or determination of whether or not a patient is sufferingfrom a PGD₂-dependent or PGD₂ mediated disease or condition byadministering to the subject a compound of Formula (I) or pharmaceuticalcomposition or medicament which includes a compound of Formula (I) anddetermining whether or not the patient responds to the treatment.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. Such kits cancomprise a carrier, package, or container that is compartmentalized toreceive one or more containers such as vials, tubes, and the like, eachof the container(s) comprising one of the separate elements to be usedin a method described herein. Suitable containers include, for example,bottles, vials, syringes, and test tubes. The containers are formed fromany acceptable material including, e.g., glass or plastic.

For example, the container(s) can comprise one or more compoundsdescribed herein, optionally in a composition or in combination withanother agent as disclosed herein. The container(s) optionally have asterile access port (for example the container can be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). Such kits optionally comprising a compound with anidentifying description or label or instructions relating to its use inthe methods described herein.

A kit will typically comprise one or more additional containers, eachwith one or more of various materials (such as reagents, optionally inconcentrated form, and/or devices) desirable from a commercial and userstandpoint for use of a compound described herein. Non-limiting examplesof such materials include, but not limited to, buffers, diluents,filters, needles, syringes; carrier, package, container, vial and/ortube labels listing contents and/or instructions for use, and packageinserts with instructions for use. A set of instructions will alsotypically be included.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself; a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

EXAMPLES

These examples are provided for illustrative purposes only and not tolimit the scope of the claims provided herein.

Example 1 Synthesis ofN-{3-tert-Butylsulfanylmethyl-4-[4-(2H-tetrazol-5-ylmethyl)-pyrazol-1-ylmethyl]-phenyl}-2,2-dimethyl-propionamide(Compound 1-1)

Step 1: 4-Methyl-pyrazole-1-carboxylic acid tert-butyl ester

To 4-methylpyrazole (0.60 mL, 7.5 mmol) and triethylamine (2.6 mL, 18.8mmol) in CH₂Cl₂ (75 mL) was added di-tert-butyl dicarbonate (1.8 g, 8.3mmol), and the reaction was stirred for 1 hour at room temperature.4-Dimethylaminopyridine (0.03 g, 0.25 mmol) was added, and the reactionwas stirred for another 2 hours, until no starting material was seen byanalytical tlc. After aqueous work-up, the crude material was purifiedby silica gel chromatography (0-100% EtOAc in hexanes) to give the titlecompound.

Step 2: 4-Bromomethyl-pyrazole-1-carboxylic acid tert-butyl ester

4-Methyl-pyrazole-1-carboxylic acid tert-butyl ester (0.875 g, 4.8mmol), N-bromosuccinimide (0.897 g, 5.0 mmol), and benzoyl peroxide(0.058 g, 0.24 mmol) were combined in CCl₄ (50 mL). The reaction washeated to reflux and stirred under a halogen lamp for 1 hour. Themixture was filtered and concentrated, and the residue was purified bysilica gel chromatography to give the title compound, contaminated witha small amount of starting material.

Step 3: 4-Cyanomethyl-pyrazole-1-carboxylic acid tert-butyl ester

To 4-bromomethyl-pyrazole-1-carboxylic acid tert-butyl ester (1.0 g, 3.5mmol) in DMSO (25 mL) was added potassium cyanide (0.228 g, 3.5 mmol),and the reaction was stirred for 15 minutes at room temperature. Themixture was poured into H₂O and extracted with EtOAc. The combinedorganic layers were dried and concentrated to give the title compound,along with some starting material and the unbrominated starting materialfrom the previous step. The material was dissolved in DMSO (10 mL), andpotassium cyanide (0.100 g, 1.5 mmol) was added. The reaction wasstirred for 1 hour at room temperature, and then worked-up, dried, andconcentrated to give the title compound, contaminated with a smallamount of 4-methyl-pyrazole-1-carboxylic acid tert-butyl ester.

Step 4: (1H-Pyrazol-4-yl)-acetonitrile

4-Cyanomethyl-pyrazole-1-carboxylic acid tert-butyl ester (3.5 mmol) inCH₂Cl₂ (10 mL) was treated with 50% trifluoroacetic acid in CH₂Cl₂ (3mL) and stirred for 30 minutes at room temperature. The mixture wasdiluted with toluene (50 mL) and concentrated to dryness to give thetitle compound.

Step 5: 2-Methyl-4-nitro-benzoic acid ethyl ester

2-Methyl-4-nitrobenzoic acid (10 g, 55.2 mmol) in EtOH (200 mL) wastreated with sulfuric acid (2 mL) and stirred at reflux until thereaction was complete. The mixture was worked-up and purified to givethe title compound.

Step 6: 2-Bromomethyl-4-nitro-benzoic acid ethyl ester

2-Methyl-4-nitro-benzoic acid ethyl ester (6.0 g, 28.7 mmol),N-bromosuccinimide (5.4 g, 30.3 mmol), and benzoyl peroxide (0.695 g,2.87 mmol) were combined in CCl₄ (250 mL). The reaction was heated toreflux and stirred under a halogen lamp overnight. After aqueouswork-up, the residue was purified by silica gel chromatography to givethe title compound.

Step 7: 2-tert-Butylsulfanylmethyl-4-nitro-benzoic acid ethyl ester

2-Bromomethyl-4-nitro-benzoic acid ethyl ester (8.0 g, 27.8 mmol) and2-methyl-2-propanethiol (3.74 mL, 33.3 mmol) were combined in MeCN (100mL) at 0° C. Sodium hydride (60% in mineral oil; 1.39 g, 34.8 mmol) wasadded, and the reaction was stirred for 5 minutes at 0° C., and then atroom temperature until no starting material was seen by analytical tlc.The mixture was quenched by adding ice chips and diluted with H₂O (100mL) and 1N aqueous HCl (30 mL), and then extracted with EtOAc. Thecombined organic layers were washed with H₂O, dried, filtered, andconcentrated, and the residue was purified by silica gel chromatographyto give the title compound.

Step 8: 4-Amino-2-tert-butylsulfanylmethyl-benzoic acid ethyl ester

2-tert-Butylsulfanylmethyl-4-nitro-benzoic acid methyl ester (5.68 g,19.1 mmol), 1,1-dimethylhydrazine (11.6 mL, 192 mmol), and DARCO (2.0 g,19.1 mmol) were combined in MeOH (200 mL). Ferric chloride (0.50 g, 3.1mmol) was added, and the reaction was stirred at 70° C. for 3.5 hours.The mixture was stored in the freezer overnight, and then worked-up andpurified by silica gel chromatography to give the title compound.

Step 9:2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-benzoic acidethyl ester

4-Amino-2-tert-butylsulfanylmethyl-benzoic acid methyl ester (5.1 g,19.1 mmol) and triethylamine (6.6 mL, 47.8moml) were combined in CH₂Cl₂(200 mL) and cooled to 0° C. Pivaloyl chloride (2.8 mL, 22.9 mmol) wasadded dropwise by syringe, and the reaction was stirred at roomtemperature for 1 hour. The mixture was worked up with EtOAc and H₂O togive the title compound.

Step 10:N-(3-tert-Butylsulfanylmethyl-4-hydroxymethyl-phenyl)-2,2-dimethyl-propionamide

To 2-tert-butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-benzoicacid methyl ester (3.83 g, 10.9 mmol) in THF (100 mL) at −10° C. wasadded lithium triethylborohydride (1M in THF; 24 mL, 24.0 mmol) slowlyvia syringe. The reaction was allowed to warm to room temperature andstirred for 45 minutes. Analytical LCMS indicated that starting materialstill remained, so the mixture was cooled to 0° C., and additionallithium triethylborohydride (1M in THF; 12 mL, 12.0 mmol) was added. Thereaction was warmed to room temperature, but analytical LCMS indicatedthat starting material still remained. The mixture was cooled to 0° C.and additional lithium triethylborohydride (1M in THF; 5 mL, 5.0 mmol)was added. The reaction was stirred at room temperature for 1.5 hours,and then the mixture was worked-up and purified to give the titlecompound.

Step 11:N-(4-Bromomethyl-3-tert-butylsulfanylmethyl-phenyl)-2,2-dimethyl-propionamide

ToN-(3-tert-butylsulfanylmethyl-4-hydroxymethyl-phenyl)-2,2-dimethyl-propionamide(1.6 g, 5.17 mmol) in DME (60 mL) at 0° C. was added phosphorustribromide (0.54 mL, 5.69 mmol) slowly via syringe. The reaction wasstirred at 0° C. for 20 minutes, until no starting material was seen byanalytical tlc. The mixture was quenched with H₂O and diluted with EtOAc(300 mL) and H₂O (100 mL). The organic layer was separated and washedwith H₂O, and then dried, filtered, and concentrated to give the titlecompound.

Step 12:N-[3-tert-Butylsulfanylmethyl-4-(4-cyanomethyl-pyrazol-1-ylmethyl)-phenyl]-2,2-dimethyl-propionamide

(1H-Pyrazol-4-yl)-acetonitrile (0.19 g, 1.77 mmol) andN-(4-bromomethyl-3-tert-butylsulfanylmethyl-phenyl)-2,2-dimethyl-propionamide(0.20 g, 0.55 mmol) were combined in MeCN. Cesium carbonate (0.95 g,2.90 mmol) was added, and the reaction was stirred for 45 minutes atroom temperature. The mixture was worked-up and purified by silica gelchromatography to give the title compound.

Step 13:N-{3-tert-Butylsulfanylmethyl-4-[4-(2H-tetrazol-5-ylmethyl)-pyrazol-1-ylmethyl]-phenyl}-2,2-dimethyl-propionamide

ToN-[3-tert-butylsulfanylmethyl-4-(4-cyanomethyl-pyrazol-1-ylmethyl)-phenyl]-2,2-dimethyl-propionamide(0.015 g, 0.04 mmol) in toluene (1 mL) was added trimethylsilyl azide(0.02 mL, 0.1 mmol), followed by dibutyltin oxide (0.001 g, 0.004 mmol),and the reaction was stirred at 80° C. overnight. Starting material wasstill present, so additional trimethylsilyl azide (0.20 mL, 1.1 mmol)and dibutyltin oxide (0.005 g, 0.02 mmol) were added, and the reactionwas stirred for 6 hours at 100° C. After work-up, the crude material waspurified by preparative HPLC to give the title compound.

Example 2 Synthesis of{1-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-benzyl]-1H-pyrazol-4-yl}-aceticacid (Compound 1-2)

Step 1:{1-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-benzyl]-1H-pyrazol-4-yl}-aceticacid ethyl ester

N-[3-tert-Butylsulfanylmethyl-4-(4-cyanomethyl-pyrazol-1-ylmethyl)-phenyl]-2,2-dimethyl-propionamide(0.080 g, 0.20 mmol) in EtOH (10 mL) was treated with sulfuric acid (10drops) and stirred at 50° C. for 2 hours. No reaction was observed, soadditional sulfuric acid (0.5 mL) was added, and the reaction wasstirred at 62° C. overnight. A small amount of product was observed, sothe mixture was diluted with H₂O and extracted with EtOAc to isolate amixture of starting material and product. The mixture was dissolved inEtOH (10 mL) and treated with acetyl chloride (0.29 mL, 4.0 mmol). Thereaction was stirred overnight at 62° C., after which time the reactionwas complete. The mixture was partitioned between EtOAc and H₂O, and theorganic layer was separated and purified by preparative HPLC to give thetitle compound.

Step 2:{1-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-benzyl]-1H-pyrazol-4-yl}-aceticacid

{1-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-benzyl]-1H-pyrazol-4-yl}-aceticacid ethyl ester (0.038 g, 0.09 mmol) in MeOH and H₂O was hydrolyzedwith lithium hydroxide to give the title compound.

Example 3 Synthesis of{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-benzyl]-[1,2,4]oxadiazol-5-yl}-aceticacid (Compound 1-3)

Step 1:N-(3-tert-Butylsulfanylmethyl-4-cyanomethyl-phenyl)-2,2-dimethyl-propionamide

N-(4-Bromomethyl-3-tert-butylsulfanylmethyl-phenyl)-2,2-dimethyl-propionamide(1.8 g, 4.8 mmol) in DMSO (40 mL) was treated with potassium cyanide(0.325 g, 5.0 mmol), and the reaction was stirred for 1 hour at roomtemperature. The mixture was worked-up and purified by silica gelchromatography to give the title compound.

Step 2:N-[3-tert-Butylsulfanylmethyl-4-(N-hydroxycarbamimidoylmethyl)-phenyl]-2,2-dimethyl-propionamide

ToN-(3-tert-butylsulfanylmethyl-4-cyanomethyl-phenyl)-2,2-dimethyl-propionamide(0.161 g, 2.3 mmol) in MeOH was added hydroxylamine hydrochloride (0.161g, 2.3 mmol) and sodium carbonate (0.245 g, 2.3 mmol), and the reactionwas stirred at reflux for 1 hour. The mixture was quenched with H₂O andextracted with EtOAc. Due to solubility of the product in the aqueouslayer, the reaction mixture was concentrated, and the residue waspurified by preparative HPLC to give the title compound as a TFA salt.The product was converted to the free base by treatment with aqueousNaHCO₃.

Step 3:{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-benzyl]-[1,2,4]oxadiazol-5-yl}-aceticacid ethyl ester

N-[3-tert-Butylsulfanylmethyl-4-(N-hydroxycarbamimidoylmethyl)-phenyl]-2,2-dimethyl-propionamide(0.10 g, 0.28 mmol) was dissolved in tert-butyl ethyl malonate (0.3 mL),and the reaction was stirred at 120° C. for 3 hours. The mixture wasquenched with H₂O and extracted with EtOAc. The combined organic layerswere dried, concentrated, and purified by preparative HPLC to give thetitle compound.

Step 4:{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-benzyl]-[1,2,4]oxadiazol-5-yl}-aceticacid

{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-benzyl]-[1,2,4]oxadiazol-5-yl}-aceticacid ethyl ester (0.28 mmol) in MeOH (5 mL) was treated with 1N aqueousLiOH (0.5 mL), and the reaction was stirred for 6 hours at roomtemperature. The mixture was diluted with H₂O and extracted with EtOAc.The combined organic layers were dried and concentrated to give thetitle compound.

Mass spectrometric data for compounds described in the Examples aredisplayed in Table 1.

Example 4 CRTH2 Assays Example 4a DP₂/CRTH2 Binding Assay

The ability of a compound to bind to the human DP₂ receptor is assessedvia a radioligand binding assay using [³H]PGD₂. HEK293 cells stablyexpressing recombinant human DP₂ are resuspended in 10 mM Hepes, 7.4containing 1 mM DTT, lysed and centrifuged at 75,000×g to pellet themembranes. The membranes are resuspended in 10 mM Hepes, 7.4 containing1 mM DTT and 10% glycerol to approximately 5 mg protein/ml. Membranes(2-10 μg protein/well) are incubated in 96-well plates with 1 nM[³H]PGD₂ and test compound in Assay Buffer (50 mM Hepes, 10 mM MnCl₂, 1mM EDTA, plus or minus 0.2% human serum albumin, pH 7.4) for 60 minutesat room temperature. The reactions are terminated by rapid filtrationthrough Whatman GF/C glass fibre filter plates. The filter plates werepre-soaked in 0.33% polythylenimine for 30 minutes at room temperaturethen washed in Wash Buffer (50 mM Hepes, 0.5 M NaCl pH 7.4) prior toharvesting. After harvesting, the filter plates are washed 3 times with1 ml cold Wash Buffer then dried. Scintillant is then added to theplates and the radioactivity retained on the filters is determined on aPackard TopCount (Perkin Elmer). Specific binding is determined as totalradioactive binding minus non-specific binding in the presence of 10 μMPGD₂. IC₅₀s were determined using GraphPad prism analysis of drugtitration curves. Tested compounds in Table 1 have IC₅₀<50 μM in thisassay.

Example 4b GTPγS Binding Assay

The ability of a compound to inhibit binding of GTP to DP₂ is assessedvia a membrane GTPγS assay. CHO cells stably expressing the recombinanthuman CRTH2 receptor are resuspended in 10 mM Hepes, 7.4 containing 1 mMDTT, lysed and centrifuged at 75,000×g to pellet the membranes. Themembranes are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT and10% glycerol. Membranes (−12.5 μg per well) are incubated in 96-wellplates with 0.05 nM [³⁵S]-GTPγS, 80 nM PGD₂, 5 μM GDP, and test compoundin Assay Buffer (50 mM Hepes, pH 7.4, 100 mM NaCl, 5 mM MgCl₂ and 0.2%human serum albumin) for 60 minutes at 30° C. The reactions areterminated by rapid filtration through Whatman GF/B glass fibre filterplates. The filter plates are washed 3 times with 1 ml cold Assay Bufferand dried. Scintillant is then added to the plates and the radioactivityretained on the filters is determined on a Packard TopCount (PerkinElmer). Specific binding is determined as total radioactive bindingminus non-specific binding in the absence of the ligand (80 nM PGD₂).IC₅₀s were determined using Graphpad prism analysis of drug titrationcurves.

Example 4c Whole Blood Esoinophil Shape Change Assay

Blood is drawn from consenting human volunteers in EDTA vacutainer tubesand used within 1 hr of draw. A 98 μl aliquot of blood is mixed with 2μl of test compound (in 50% DMSO) in 1.2 ml polypropylene tubes. Theblood is vortexed and incubated at 37° C. for 15 minutes. 5 μl of 1 μMPGD₂ in PBS is added for a final concentration of 50 nM and the tubesbriefly vortexed. The reactions are incubated for exactly 5 minutes at37° C. and then terminated by placing the tubes on ice and immediatelyadding 250 μl of ice-cold 1:4 diluted Cytofix (BD Biosciences). Thereactions are transferred to 12×75 mM polystyrene round bottom tubes andthe red blood cells lysed by the addition of 3 ml ammonium chloridelysing solution (150 mM NH₄Cl, 10 mM KHCO₃, 0.1 mM EDTA disodium salt)and incubation at room temperature for 15 minutes. The cells arepelleted by spinning at 1300 rpm for 5 minutes at 4° C. and washed oncewith 3 ml ice-cold PBS. The cells are resuspended in 0.2 ml of ice-cold1:4 diluted Cytofix (BD Biosciences) and analyzed on a FACSCalibur (BDBiosciences) within 2 hours. Eosinophils were gated on the basis ofautofluorescence in the FL2 channel and shape change on 500 eosinophilswas assayed by forward scatter and side scatter analysis. The specificchange in shape induced by PGD₂ was calculated as the difference betweenthe percentage of high forward scatter eosinophils in the presence andabsence of PGD₂. IC₅₀s were determined using Graphpad Prism® analysis ofdrug titration curves.

Example 4d DP₁ Binding Assay

The ability of a compound to bind to the human DP1 receptor wasevaluated via a radioligand membrane binding assay using the DP₁selective synthetic ligand [³H]BW A868C. Packed human platelets(Biological Specialty Corporation), were resuspended in 6 volumes ofHepes/HBSS buffer (10 mM Hepes, 1 mM DTT in Hanks Balanced Salt Solution(HBSS)), lysed and centrifuged at 75,000×g to pellet the membranes.Membranes were resuspended in Hepes/HBSS buffer to approximately 12 mgprotein/ml. Membranes (20 μg protein/well) are incubated in 96-wellplates with 2 nM [³H]BWA868C and test compound in Assay Buffer (50 mMHepes, 10 mM MnCl₂, 1 mM EDTA, plus or minus 0.2% human serum albumin,pH 7.4) for 60 minutes at room temperature. The reactions are terminatedby rapid filtration through Whatman GF/C glass fibre filter plates. Thefilter plates were pre-soaked in 0.33% polethylenimine for 30 minutes atroom temperature then washed in Wash Buffer (50 mM Hepes, 0.5 M NaCl pH7.4) prior to harvesting. After harvesting, the filter plates are washed3 times with 1 ml cold Wash Buffer then dried. Scintillant is then addedto the plates and the radioactivity retained on the filters isdetermined on a Packard TopCount (Perkin Elmer). Specific binding isdetermined as total radioactive binding minus non-specific binding inthe presence of 10 μM BW A868C. IC₅₀s were determined using GraphPadprism analysis of drug titration curves.

Example 5 In Vivo Assay Mouse Allergic Rhinitis Model

The compounds ability to inhibit allergen-induced sneezing and nasalrubbing is assessed using a mouse model of allergic rhinitis. Methodswere adapted from those detailed in Nakaya, M., et al. 2006. Noninvasivesystem for evaluating allergen-induced nasal hypersensitivity in murineallergic rhinitis. Laboratory Investigation, 86:917-926. Female BALB/cmice (20-25 g) are immunized by an intraperitoneal injection (i.p.) of 2μg ovalbumin (OVA) complexed with alum in a volume 0.2 ml on days 0 and14. Seven days later (day 21) mice are challenged intranasally with 20μl of a 10 mg/ml solution of OVA. The challenge period occurs daily fromdays 21 to day 25. Mice (5/group) are randomly assigned to receiveeither compound or vehicle and are treated by oral gavage 1-2 hour priorto each OVA challenge. The number of sneezes and nasal rubs are countedby an independent blind observe during a period of 8 minutes immediatelyfollowing OVA challenge on days 21, 23 and 25. A significant increase inallergen-induced sneezing and nasal rubbing occurs over the 5-daychallenge period. Inhibition of this effect by select compounds isdetermined statistically using Graphpad prism.

Example 6 Guinea Pig IV-DKPGD2-Induced Peripheral Blood Leukocyte Influx

The compounds ability to inhibit leukocyte migration in vivo wasassessed using intravenous injection of13,14-dihydro-15-keto-prostaglandin D2 (DK-PGD2). Methods were adaptedfrom those detailed Shichijo et al., 2003, Chemoattractantreceptor-homologous molecule expressed on Th2 cells activation in vivoincreases blood leukocyte counts and its blockade abrogates13,14-dihydro-15-keto-prostaglandin D2-induced eosinophilia in rats.Journal of Pharmacology and Experimental Therapeutics, 307:518-525. MaleHartley guinea pigs were immunized with ovalbumin (OVA) on day 0 byintraperitoneal (IP) injection of 1 ml of a 100 μg/ml solution in ImjectAlum. They were then used in the DK-PGD2 procedure between days 14 and21. Subjects were randomly assigned to receive either vehicle (0.5%methyl cellulose, 4 ml/kg, oral (PO)) or one of three to four doses oftest compound. Two hours or eighteen hours after dosing, animals wereanesthetized with ketamine and challenged with DK-PGD₂ (1 mg/kg, IV).Thirty minutes after IV administration, blood was collected via themarginal ear vein into EDTA tubes for cell analysis. 10 μl blood waslysed in 1901 water followed by a further 20-fold dilution in PBS. A 10μl fraction was mixed with equal parts trypan blue and loaded on ahemocytometer. Cells were visualized at a magnification of 40× using aLabPro light microscope and totals counted and recorded. Cells areexpressed as total cells×10⁸ per ml of blood. Inhibition of this effectby select compounds is determined statistically using Graphpad prism.

Example 7 Clinical Trials in Humans Study 1: Clinical Trial EvaluatingEffect of Compound of Formula (I) on Ex Vivo PGD₂-Induced BloodEosinophil Shape Change

In this double-blind, randomized, placebo-controlled, single ascendingdose study of Compound of Formula (I) in healthy volunteers theinhibition of ex vivo PGD₂-induced blood eosinophil shape change isdetermined to show proof of biochemical mechanism of DP2 receptorantagonism. Eight subjects (6 active, 2 placebo) per dose level areused. Pre dose blood is drawn and challenged with PGD₂ to determinebaseline shape change as described above in Example 4. At varying timesafter dosing blood is drawn for both pharmacokinetic analyses of drugconcentration in blood, and also for PGD₂ challenge and eosinophil shapechange determination. The extent of receptor blockage is determined fromthe relationship between drug blood concentration and percentageinhibition of eosinophil shape change.

Study 2: Clinical Trial Evaluating Effect of Compound of Formula (I) onAllergen-Induced Nasal Symptoms and Inflammatory and Allergic Biomarkers

In this double-blind, randomized, placebo-controlled study of Compoundof Formula (I) in individuals with allergic rhinitis the inhibition ofnasal symptoms and allergic biomarkers is determined following nasalchallenge with appropriate allergen. Fifteen subjects (10 active, 5placebo) are used. Subjects are dosed for 7 days with either placebo oran amount of compound of formula (I) that results in complete DP2receptor block in an ex vivo PGD₂-induced blood eosinophil shape changepharmacodynamic study as described above. On day 7 subjects undergonasal allergen challenge (2 hours post-dose) and early allergic response(0.25-1.0 hr) and late allergic response (4-24 hr) are evaluated as anincrease from baseline for treated vs placebo. In addition changes ininflammatory cell differentials, Th2 cytokines and other inflammatorymarkers are determined as increase from baseline for treated vs placebo.

Compound of Formula (I) Assay

The plasma concentrations of compound of Formula (I) are determined byLCMS-MS giving a detection limit in the range of 1-40 ng·ml-1

Study 3: Vienna Challenge Chamber Study

Study design: The study is a randomised, double blind, placebocontrolled, two way crossover evaluation of compound of Formula (I),Formula (II) or Formula (III) given orally for eight days. There is ascreening period of one week and a washout period of three weeks betweenthe two treatment periods.

There is a follow up one week after the last dose of study drug. Thegroup of patients who receive the study drug for the first treatmentperiod and placebo for the second are designated group A, while thegroup of patients who receive placebo for the first treatment period andthe study drug for the second treatment period are designated group B.

Treatment plan and methods: The subjects undergo a complete screeningassessment to determine a baseline response to allergens. This screeningassessment takes place one week prior to the start of dosing.

Subjects commence dosing with compound of Formula (I), Formula (II) orFormula (III) or placebo on Day 1 of each treatment period of the study.Adverse events, total nasal symptom score and concomitant medicationsare noted.

Subjects report back to the clinic on Day 2 of each treatment period fora 6 hour allergen challenge. The following measurements are obtained:

-   -   Total nasal symptom score (TNSS) (obstruction, rhinorrhoea,        itch, sneeze) with each symptom scored on a categorical scale        from 0 to 3 pre-challenge, every 15 mins from 0 to 6 h        post-start of challenge    -   Eye symptom score (watery eyes, itchy eyes, red eyes) with each        symptom scored on a categorical scale from 0 to 3 pre-challenge,        every 15mins from 0 to 6 h post-start of challenge    -   Other symptoms (cough, itchy throat, itchy ears) with each        symptom scored on a categorical scale from 0 to 3 pre-challenge        and every 15mins from 0 to 6 h post-start of challenge

Subjects report back to the clinic on Day 8 of each treatment period fora 6 hour allergen challenge and the measurements obtained on Day 2 arerepeated.

A final follow-up visit is conducted one week after the last dose oftest article in Treatment Period 2.

Example 8 Pharmaceutical Compositions Example 8a Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of Formula (I) is dissolved in sterile water and then mixedwith 10 mL of 0.9% sterile saline. The mixture is incorporated into adosage unit form suitable for administration by injection.

Example 8b Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of Formula (I) is mixed with 750 mg of starch. The mixture isincorporated into an oral dosage unit for, such as a hard gelatincapsule, which is suitable for oral administration.

Example 8c Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, mix 100 mg of a compound of Formula (I) with 420 mg ofpowdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 mL distilledwater, and 0.42 mL mint extract. The mixture is gently blended andpoured into a mold to form a lozenge suitable for buccal administration.

Example 8d Fast-Disintegrating Sublingual Tablet

A fast-disintegrating sublingual tablet is prepared by mixing 48.5% byweigh of a compound of Formula (I), 44.5% by weight of microcrystallinecellulose (KG-802), 5% by weight of low-substituted hydroxypropylcellulose (50 μm), and 2% by weight of magnesium stearate. Tablets areprepared by direct compression (AAPS PharmSciTech. 2006; 7(2):E41). Thetotal weight of the compressed tablets is maintained at 150 mg. Theformulation is prepared by mixing the amount of compound of Formula (I)with the total quantity of microcrystalline cellulose (MCC) andtwo-thirds of the quantity of low-substituted hydroxypropyl cellulose(L-HPC) by using a three dimensional manual mixer (Inversina®,Bioengineering AG, Switzerland) for 4.5 minutes. All of the magnesiumstearate (MS) and the remaining one-third of the quantity of L-HPC areadded 30 seconds before the end of mixing.

Example 8e Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound of Formula (I) is mixed with 50 mg of anhydrous citricacid and 100 mL of 0.9% sodium chloride solution. The mixture isincorporated into an inhalation delivery unit, such as a nebulizer,which is suitable for inhalation administration.

Example 8f Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of acompound of Formula (I) is mixed with 2.5 g of methylcelluose (1500mPa), 100 mg of methylparapen, 5 g of glycerin and 100 mL of purifiedwater. The resulting gel mixture is then incorporated into rectaldelivery units, such as syringes, which are suitable for rectaladministration.

Example 8g Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound of Formula (I) is mixed with 1.75 g of hydroxypropyl celluose,10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL ofpurified alcohol USP. The resulting gel mixture is then incorporatedinto containers, such as tubes, which are suitable for topicaladministration.

Example 8h Ophthalmic Solution Composition

To prepare a pharmaceutical ophthalmic solution composition, 100 mg of acompound of Formula (I) is mixed with 0.9 g of NaCl in 100 mL ofpurified water and filtered using a 0.2 micron filter. The resultingisotonic solution is then incorporated into ophthalmic delivery units,such as eye drop containers, which are suitable for ophthalmicadministration.

Example 81 Nasal Spray Solution

To prepare a pharmaceutical nasal spray solution, 10 g of a compound ofFormula (I) is mixed with 30 mL of a 0.05M phosphate buffer solution (pH4.4). The solution is placed in a nasal administrator designed todeliver 100 μl of spray for each application.

Example 8j Clear Scalp Lotion

Dissolve 500 mg of a compound of Formula (I) in 10 mL of 95% ethanol.Add 50 mL of ethoxy diglycol. Dissolve 50 mg of methylparaben and 20 mgof propylparaben in 1 mL of propylene glycol and add to the ethanolsolution. Add approximately 100 mL of purified water and mix well.

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

1. A compound having the structure of Formula (I), pharmaceuticallyacceptable salt, or N-oxide, thereof:

wherein, ring A is a substituted or unsubstituted heteroarylene, where—X— and —C(R¹)₂Q are on non-adjacent atoms of ring A, wherein if ring Ais substituted, then each substituent on ring A is independentlyselected from H and R^(A); Q is —C(═O)-Q¹, tetrazolyl, or a carboxylicacid bioisostere; Q¹ is —OR¹⁵, —NHSO₂R⁹, —N(R¹⁰)₂, —NH—OH, or —NH—CN; Xis —O—, —S—, —S(═O)—, —S(═O)₂—, —NR¹³—, —C(R¹⁶)₂—, or —C(═O)—; each R¹is independently selected from H, halogen, C₁-C₄alkyl, andC₁-C₄haloalkyl; each of R², R³, R⁴ and R⁵ is independently selected fromH, halogen, —CN, —NO₂, —OH, —OR¹⁰, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹,—N(R¹⁰)S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —OCO₂R¹⁰,—N(R¹⁰)₂, —NHCH₂CO₂R¹⁰, —OCH₂CO₂R¹⁰, —SCH₂CO₂R¹⁰, —C(═O)N(R¹⁰)₂,—OC(═O)N(R¹⁰)₂, —NR¹⁰C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R⁹,—NR¹⁰—C₁-C₄alkylene-C(═O)R⁹, —NR¹⁰C(═O)OR⁹, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, asubstituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted orunsubstituted C₂-C₁₀heterocycloalkyl, a substituted or unsubstitutedaryl, and a substituted or unsubstituted heteroaryl; each R^(A) isindependently selected from H, halogen, —CN, —NO₂, —OH, —OR¹⁰, —SR⁹,—S(═O)R⁹, —S(═O)₂R⁹, —N(R¹⁰)S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹,—OC(═O)R⁹, —CO₂R¹⁰, —OCO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —OC(═O)N(R)₂,—NR¹⁰C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R⁹, —NR¹⁰C(═O)OR⁹, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, asubstituted or unsubstituted C₃-C₁₀cycloalkyl, and a substituted orunsubstituted C₂-C₁₀heterocycloalkyl; each R⁶ is H; Z is —N—R⁷—, —S—,—S(═O)—, —S(═O)₂— or —O—; R⁷ is —C(═O)R¹¹, —C(═O)OR¹², —C(═O)N(R¹³)₂,—S(═O)₂N(R¹³)₂ or —S(═O)₂R¹²; R¹¹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, a substituted or unsubstituted C₃-C₁₀cycloalkyl, asubstituted or unsubstituted C₂-C₁₀heterocycloalkyl, a substituted orunsubstituted aryl, a substituted or unsubstituted heteroaryl,—C₁-C₆alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),—C₁-C₆alkylene-(substituted or unsubstituted C₂-C₁₀heterocycloalkyl),—C₁-C₆alkylene-(substituted or unsubstituted aryl) or—C₁-C₆alkylene-(substituted or unsubstituted heteroaryl); or R¹¹ is-L³-X³-Q³; L³ is a —C₁-C₆alkylene-; X³ is a bond, —O—, —S—, —S(═O)—,—S(═O)₂—, or —NR¹³—; Q³ is a C₁-C₆alkyl, C₁-C₆fluoroalkyl a substitutedor unsubstituted C₃-C₁₀ cycloalkyl, a substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, asubstituted or unsubstituted heteroaryl, —C₁-C₆alkylene-(substituted orunsubstituted C₃-C₁₀cycloalkyl), —C₁-C₆alkylene-(substituted orunsubstituted C₂-C₁₀heterocycloalkyl), —C₁-C₆alkylene-(substituted orunsubstituted aryl), or C₁-C₆alkylene-(substituted or unsubstitutedheteroaryl); R¹² is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, asubstituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted orunsubstituted C₂-C₁₀heterocycloalkyl, a substituted or unsubstitutedaryl, a substituted or unsubstituted heteroaryl,—C₁-C₆alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),—C₁-C₆alkylene-(substituted or unsubstituted C₂-C₁₀heterocycloalkyl),—C₁-C₆alkylene-(substituted or unsubstituted aryl) or—C₁-C₆alkylene-(substituted or unsubstituted heteroaryl); each R¹³ isindependently H, —CN, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, asubstituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted orunsubstituted C₂-C₁₀heterocycloalkyl, a substituted or unsubstitutedaryl, a substituted or unsubstituted heteroaryl,—C₁-C₆alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),—C₁-C₆alkylene-(substituted or unsubstituted C₂-C₁₀heterocycloalkyl),—C₁-C₆alkylene-(substituted or unsubstituted aryl) or—C₁-C₆alkylene-(substituted or unsubstituted heteroaryl); or two R¹³groups attached to the same N atom are taken together with the N atom towhich they are attached to form a substituted or unsubstitutedheterocycle; R⁸ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl, asubstituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted orunsubstituted C₂-C₁₀heterocycloalkyl, a substituted or unsubstitutedaryl, or a substituted or unsubstituted heteroaryl, —C₁-C₆alkylene-R¹⁴,—C₁-C₆alkylene-O—R¹⁴, —C₁-C₆alkylene-S—R¹⁴, —C₁-C₆alkylene-S(═O)—R¹⁴,—C₁-C₆alkylene-S(═O)₂—R¹⁴, —C₁-C₆alkylene-N(R¹⁴)₂,—C₁-C₆alkylene-C(═O)—R¹⁴, —C₁-C₆alkylene-C(═O)O—R¹⁴—,—C₁-C₆alkylene-OC(═O)—R¹⁴, —C₁-C₆alkylene-NR¹⁴C(═O)—R¹⁴ or—C₁-C₆alkylene-C(═O)N(R¹⁴)₂; each R¹⁴ is independently selected from H,C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl, a substituted orunsubstituted C₃-C₁₀cycloalkyl, a substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, asubstituted or unsubstituted benzyl, a substituted or unsubstitutednaphthyl, or a substituted or unsubstituted heteroaryl; or two R¹⁴groups attached to the same nitrogen are taken together with thenitrogen atom to which they are attached to form a substituted orunsubstituted heterocycle; or R⁷ and R⁸ are taken together with the Natom to which they are attached to form a substituted or unsubstitutedheterocycle; R⁹ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, asubstituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted orunsubstituted C₂-C₁₀heterocycloalkyl, a substituted or unsubstitutedaryl, a substituted or unsubstituted heteroaryl,—C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),—C₁-C₄alkylene-(substituted or unsubstituted C₂-C₁₀heterocycloalkyl),—C₁-C₄alkylene-(substituted or unsubstituted aryl), or—C₁-C₄alkylene-(substituted or unsubstituted heteroaryl); each R¹⁰ isindependently selected from H, C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆fluoroalkyl, a substituted or unsubstituted C₃-C₁₀cycloalkyl, asubstituted or unsubstituted C₂-C₁₀heterocycloalkyl, a substituted orunsubstituted aryl, a substituted or unsubstituted heteroaryl,—C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),—C₁-C₄alkylene-(substituted or unsubstituted C₂-C₁₀heterocycloalkyl),—C₁-C₄alkylene-(substituted or unsubstituted aryl), and—C₁-C₄alkylene-(substituted or unsubstituted heteroaryl); or two R¹⁰groups attached to the same N atom are taken together with the N atom towhich they are attached to form a substituted or unsubstitutedheterocycle; R¹⁵ is selected from H and C₁-C₆alkyl; and each R¹⁶ isindependently selected from H, —OH, halogen, —CN, C₁-C₆alkyl.
 2. Thecompound of claim 1, wherein: Q is —C(═O)-Q¹ or tetrazolyl; Q¹ is —OR¹⁵;each R¹ is independently selected from H, F, and —CH₃; each of R², R³,and R⁵ is independently selected from H, halogen, —CN, —NO₂, —OH, —OR¹⁰,—N(R¹⁰)₂, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy, C₁-C₄alkoxy,and C₁-C₄heteroalkyl; X is —O—, —S—, or —C(R¹⁶)₂—; each R¹⁶ isindependently selected from H and —CH₃.
 3. The compound of claim 2,wherein: Q is —C(═O)-Q¹; X is —O— or —CH₂—; each R¹ is H; at least oneof R², R³, and R⁵ are H.
 4. The compound of claim 3, wherein thecompound of Formula (I) has a structure selected from:


5. The compound of claim 4, wherein: each R¹ is H; ring A is asubstituted or unsubstituted heteroarylene selected from pyridinyl,pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thienyl, furanyl,pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl,pyrazolyl, isothiazolyl, triazolyl, tetrazolyl, wherein if ring A issubstituted, then each substituent on ring A is independently selectedfrom H and R^(A); each R^(A) is independently selected from H, halogen,—CN, —OH, —OR¹⁰, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹, —C(═O)R⁹, —N(R¹⁰)₂,C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, and C₁-C₆alkoxy; R⁴ isselected from halogen, —CN, —NO₂, —OH, —OR¹⁰, —S(═O)₂R⁹, —NHS(═O)₂R⁹,—N(C₁-C₆alkyl)S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰,—OCO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —OC(═O)N(R¹⁰)₂, —NHC(═O)N(R¹⁰)₂,—N(C₁-C₄alkyl)C(═O)N(R¹⁰)₂, —NHC(═O)R⁹, —N(C₁-C₄alkyl)C(═O)R⁹,—NH—C₁-C₄alkylene-C(═O)R⁹, —NHC(═O)OR⁹, —N(C₁-C₄alkyl)C(═O)OR⁹,C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy,C₁-C₆heteroalkyl, a substituted or unsubstituted C₃-C₆cycloalkyl, asubstituted or unsubstituted C₂-C₆heterocycloalkyl, a substituted orunsubstituted phenyl, and a substituted or unsubstituted monocyclicheteroaryl; R⁹ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₃-C₆cycloalkyl, asubstituted or unsubstituted phenyl, a substituted or unsubstitutedmonocyclic heteroaryl, —C₁-C₂alkylene-C₃-C₆cycloalkyl,—C₁-C₂alkylene-(substituted or unsubstituted phenyl), or—C₁-C₄alkylene-(substituted or unsubstituted monocyclic heteroaryl);each R¹⁰ is independently selected from H, C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, a substituted orunsubstituted monocyclic heteroaryl, —C₁-C₂alkylene-(C₃-C₆cycloalkyl),—C₁-C₂alkylene-(substituted or unsubstituted phenyl), and—C₁-C₂alkylene-(substituted or unsubstituted heteroaryl); R¹⁵ is H. 6.The compound of claim 5, wherein: R⁴ is selected from —NHS(═O)₂R⁹,—N(R¹⁰)₂, —NHC(═O)N(R¹⁰)₂, —NHC(═O)R⁹, and —NHC(═O)OR⁹; R⁹ isC₁-C₆alkyl, C₁-C₆fluoroalkyl, C₃-C₆cycloalkyl, a substituted orunsubstituted phenyl, a substituted or unsubstituted monocyclicheteroaryl, —C₁-C₂alkylene-C₃-C₆cycloalkyl, —C₁-C₂alkylene-(substitutedor unsubstituted phenyl), or —C₁-C₄alkylene-(substituted orunsubstituted monocyclic heteroaryl); each R¹⁰ is independently selectedfrom H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₃-C₆cycloalkyl, a substituted orunsubstituted phenyl, a substituted or unsubstituted monocyclicheteroaryl, —C₁-C₂alkylene-(C₃-C₆cycloalkyl),—C₁-C₂alkylene-(substituted or unsubstituted phenyl), and—C₁-C₂alkylene-(substituted or unsubstituted heteroaryl).
 7. (canceled)8. (canceled)
 9. (canceled)
 10. The compound of claim 5, wherein: Z is—S—, —S(═O)—, or —S(═O)₂—; R⁸ is C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl,a substituted or unsubstituted monocyclic heteroaryl,—C₁-C₄alkylene-R¹⁴, —C₁-C₄alkylene-O—R¹⁴, —C₁-C₄alkylene-N(R¹⁴)₂,—C₁-C₄alkylene-C(═O)—R¹⁴, —C₁-C₄alkylene-C(═O)O—R¹⁴—, or—C₁-C₄alkylene-C(═O)N(R¹⁴)₂; each R¹⁴ is independently selected from H,C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl, a substituted orunsubstituted C₃-C₆cycloalkyl, a substituted or unsubstituted phenyl, asubstituted or unsubstituted benzyl, a substituted or unsubstitutednaphthyl, or a substituted or unsubstituted monocyclic heteroaryl; ortwo R¹⁴ groups attached to the same nitrogen are taken together with thenitrogen atom to which they are attached to form a substituted orunsubstituted C₃-C₆heterocycloalkyl.
 11. The compound of claim 10,wherein: R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl, asubstituted or unsubstituted phenyl, a substituted or unsubstitutedmonocyclic heteroaryl, or —C₁-C₄alkylene-R¹⁴; R¹⁴ is C₃-C₆cycloalkyl, asubstituted or unsubstituted phenyl, or a substituted or unsubstitutedmonocyclic heteroaryl.
 12. The compound of claim 11, wherein: Z is —S—;R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl, a substituted orunsubstituted phenyl, a substituted or unsubstituted monocyclicheteroaryl, or —C₁-C₄alkylene-R¹⁴; R¹⁴ is C₃-C₆cycloalkyl, a substitutedor unsubstituted phenyl, or a substituted or unsubstituted monocyclicheteroaryl.
 13. The compound of claim 5, wherein: Z is —N—R⁷; R⁷ is—C(═O)R¹¹, —C(═O)OR¹², or —C(═O)N(R¹³)₂; R¹¹ is C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, a substituted orunsubstituted aryl, a substituted or unsubstituted heteroaryl,—C₁-C₄alkylene-(C₃-C₆cycloalkyl), —C₁-C₄alkylene-(substituted orunsubstituted phenyl) or —C₁-C₄alkylene-(substituted or unsubstitutedmonocyclic heteroaryl); or R¹¹ is -L³-X³-Q³; L³ is a —C₁-C₄alkylene-; X³is a bond, —O—, —S—, —S(═O)—, or —S(═O)₂—; Q³ is a C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₃-C₆cycloalkyl, a substituted or unsubstitutedphenyl, a substituted or unsubstituted monocyclci heteroaryl,—C₁-C₄alkylene-(C₃-C₁₀cycloalkyl), —C₁-C₄alkylene-(substituted orunsubstituted phenyl), or C₁-C₄alkylene-(substituted or unsubstitutedmonocyclic heteroaryl); R¹² is C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, a substituted or unsubstitutedphenyl, a substituted or unsubstituted monocyclic heteroaryl,—C₁-C₄alkylene-(C₃-C₆cycloalkyl), —C₁-C₄alkylene-(substituted orunsubstituted phenyl) or —C₁-C₄alkylene-(substituted or unsubstitutedmonocyclic heteroaryl); each R¹³ is independently H, —CN, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, a substituted orunsubstituted phenyl, a substituted or unsubstituted monocyclicheteroaryl, —C₁-C₄alkylene-(C₃-C₆cycloalkyl),—C₁-C₄alkylene-(substituted or unsubstituted phenyl) or—C₁-C₄alkylene-(substituted or unsubstituted monocyclic heteroaryl); ortwo R¹³ groups attached to the same N atom are taken together with the Natom to which they are attached to form a substituted or unsubstitutedmonocyclic heterocycle; R⁸ is C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, a substituted or unsubstituted C₃-C₁₀cycloalkyl, asubstituted or unsubstituted phenyl, or a substituted or unsubstitutedmonocyclic heteroaryl, or —C₁-C₄alkylene-R¹⁴; R¹⁴ is C₃-C₆cycloalkyl, asubstituted or unsubstituted phenyl, a substituted or unsubstitutednaphthyl, a substituted or unsubstituted monocyclic heteroaryl or asubstituted or unsubstituted bicyclic heteroaryl.
 14. The compound ofclaim 13, wherein: Z is —N—R⁷; and R⁷ is —C(═O)R¹¹ R¹¹ is C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₃-C₆cycloalkyl, a substituted or unsubstitutedphenyl, a substituted or unsubstituted monocyclic heteroaryl,—C₁-C₂alkylene-(C₃-C₆cycloalkyl), —C₁-C₂alkylene-(substituted orunsubstituted phenyl) or —C₁-C₂alkylene-(substituted or unsubstitutedmonocyclic heteroaryl); or R¹¹ is -L³-X³-Q³; L³ is a —C₁-C₄alkylene-; X³is a bond, —O—, —S—, —S(═O)—, or —S(═O)₂—; Q³ is a C₁-C₆alkyl, asubstituted or unsubstituted phenyl, a substituted or unsubstitutedmonocyclic heteroaryl, —C₁-C₄alkylene-(substituted or unsubstitutedphenyl), or C₁-C₄alkylene-(substituted or unsubstituted monocyclicheteroaryl).
 15. (canceled)
 16. (canceled)
 17. The compound of claim 13,wherein: Z is —N—R⁷; and R⁷ is —C(═O)OR¹²; R¹² is C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₃-C₆cycloalkyl, a substituted or unsubstitutedphenyl, a substituted or unsubstituted monocyclic heteroaryl,—C₁-C₂alkylene-(C₃-C₆cycloalkyl), —C₁-C₂alkylene-(substituted orunsubstituted phenyl) or —C₁-C₂alkylene-(substituted or unsubstitutedmonocyclic heteroaryl); R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl,C₃-C₆cycloalkyl, or —C₁-C₂alkylene-R¹⁴; R¹⁴ is C₃-C₆cycloalkyl, asubstituted or unsubstituted phenyl, or a substituted or unsubstitutedmonocyclic heteroaryl.
 18. The compound of claim 17, wherein: R¹² isC₁-C₆alkyl, —C₁-C₂alkylene-(substituted or unsubstituted phenyl) or—C₁-C₂alkylene-(substituted or unsubstituted monocyclic heteroaryl); R⁸is C₁-C₆alkyl, C₁-C₆haloalkyl, or C₃-C₆cycloalkyl.
 19. The compound ofclaim 13, wherein: Z is —N—R⁷; and R⁷ is —C(═O)N(R¹³)₂; each R¹³ isindependently H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₃-C₆cycloalkyl, asubstituted or unsubstituted phenyl, a substituted or unsubstitutedmonocyclic heteroaryl, —C₁-C₂alkylene-(C₃-C₆cycloalkyl),—C₁-C₂alkylene-(substituted or unsubstituted phenyl) or—C₁-C₂alkylene-(substituted or unsubstituted monocyclic heteroaryl); R⁸is C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl, a substituted orunsubstituted phenyl, or a substituted or unsubstituted monocyclicheteroaryl, or —C₁-C₂alkylene-R¹⁴; R¹⁴ is C₃-C₆cycloalkyl, a substitutedor unsubstituted phenyl, or a substituted or unsubstituted monocyclicheteroaryl.
 20. (canceled)
 21. The compound of claim 19, wherein: oneR¹³ is C₁-C₆alkyl, —C₁-C₂alkylene-(substituted or unsubstituted phenyl)or —C₁-C₂alkylene-(substituted or unsubstituted monocyclic heteroaryl)and the other R¹³ is H or C₁-C₄alkyl; R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl,C₃-C₆cycloalkyl, or —C₁-C₂alkylene-R¹⁴; R¹⁴ is a substituted orunsubstituted phenyl.
 22. The compound of claim 5, wherein: Z is —N—R⁷;and R⁷ and R⁸ are taken together with the nitrogen atom to which theyare attached to form a substituted or unsubstituted heterocycle.
 23. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1, or a pharmaceutically acceptable salt thereof,and at least one pharmaceutically acceptable inactive ingredientselected from pharmaceutically acceptable diluents, pharmaceuticallyacceptable excipients, and pharmaceutically acceptable carriers. 24.(canceled)
 25. (canceled)
 26. A method for treating a PGD₂-dependentcondition or disease in a patient comprising administering to thepatient a therapeutically effective amount of a compound of claim 1, ora pharmaceutically acceptable salt thereof.
 27. The method of claim 26,wherein the PGD₂-dependent condition or disease is selected from asthma,rhinitis, allergic conjuctivitis, atopic dermatitis, chronic obstructivepulmonary disease (COPD), pulmonary hypertension, interstitial lungfibrosis, arthritis, allergy, psoriasis, inflammatory bowel disease,adult respiratory distress syndrome, myocardial infarction, aneurysm,stroke, cancer, wound healing, endotoxic shock, pain, inflammatoryconditions, eosinophilic esophagitis, eosinophil-associatedgastrointestinal disorders (EGID), idiopathic hypereosinophilicsyndrome, otitis, airway constriction, mucus secretion, nasalcongestion, increased microvascular permeability and recruitment ofeosinophils, urticaria, sinusitis, angioedema, anaphylaxia, chroniccough and Churg Strauss syndrome.
 28. The method of claim 26, whereinthe PGD₂-dependent disease or condition is a respiratory disease orcondition.
 29. (canceled)
 30. (canceled)